Sulfonamide-containing heterocyclic compounds

ABSTRACT

The present invention provides a sulfonamide- or sulfonylurea-containing heterocyclic compounds. Specifically, it provides a heterocyclic compound represented by the formula (I), a pharmacologically acceptable salt thereof or a hydrate of them.                    
     In the formula, A is hydrogen atom, a halogen atom, a C1-C4 alkyl or alkoxy group which may be substituted with a halogen atom, or cyano group; B is an optionally substituted aryl group or monocyclic heteroaryl group, or:                    
     (wherein, the ring Q is an aromatic ring which may have nitrogen atom; and the ring M is a ring sharing a double bond with the ring Q, which ring may have a heteroatom; and the rings Q and M may share nitrogen atom); K is a single bond; T, W, X and Y are the same as or different from each other and each is ═C(D)— (wherein, D is hydrogen or a halogen atom) or nitrogen atom; U and V are the same as or different from each other and each is ═C(D)—, nitrogen atom, —CH 2 —, oxygen atom or —CO—; Z is a single bond or —CO—NH—; and R 1  is hydrogen atom, etc.

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/JP00/09326 which has an Internationalfiling date of Dec. 27, 2000, which designated the United States ofAmerica.

TECHNICAL FIELD

The present invention relates to a sulfonamide-containing heterocycliccompound which is useful as a medicament and to an antiangiogenic effectthereof. Further, it relates to an antitumor agent, a cancer metastasissuppressor, a therapeutic agent for diabetic retinopathy, a therapeuticagent for rheumatic arthritis and a therapeutic agent for hematoma onthe basis of an antiangiogenic effect.

PRIOR ART

It has become clear that there is a close relation between proliferationof cancer and angiogenesis. Thus, when angiogenesis is not generated atthe site of cancer, the cancer remains in a state of dormant tumor.However, it has become clarified that, when angiogenesis is generated,oxygen and nutrients in blood are supplied to the tumor wherebyproliferation and metastasis of cancer are promoted resulting in aclinically malignant state. Accordingly, it is expected that, whenangiogenesis of cancer is suppressed, proliferation and metastasis ofcancer can be suppressed. Since angiogenetic vessels are composed ofendothelial cells and interstitial cells of the host, target of theantiangiogenic agent is not cancer cells but such normal cells of thehost. Because of the fact that the cancer cells are not a direct target,efficacy to the cancer which does not respond to known anticancer agentscan be expected as well and, in addition, it is presumed that thepossibility of occurrence of tolerant cancer which is a big problem incancer therapy is little. In addition, angiogenesis is a tumor-specificphenomenon and, in mature individuals, it is limited to the formation ofendometrium, etc. accompanied by a menstrual cycle. Accordingly, itsadverse effect is thought to be little as compared with known anticancerdrugs. Recently, it has been experimentally proved in preclinical teststhat antiangiogenic agents are able to suppress and further to reducethe proliferation of cancer in the cancer-transplanted models and thattolerant cancer is not generated and, in clinical tests, the correlationbetween angiogenesis and malignization of many solid cancers such asbreast cancer, prostatic cancer, lung cancer and cancer of the colon hasbeen shown.

In cancer tissues, apoptosis and proliferation of cancer cellscontinuously occur and it has been known that, depending upon thebalance between them, progressive cancer or dormant tumor is resulted.An antiangiogenic agent does not directly kill the cancer cells but cutsoff the nutrient sources so that the said balance is inclined toapoptosis inducing dormant tumor or reduction in cancer whereby it is adrug which can be expected to exhibit an excellent effect (prolongationof life, inhibition of recurrence and suppression of metastasis) by along-term therapy.

In a preclinical stage, there are antiangiogenic agents by variousaction mechanisms but, since their antitumor effect in a preclinicalstage is insufficient, their usefulness in clinical stage is stilldoubtful and, therefore, there has been a brisk demand forantiangiogenic agents where the effect is reliable.

It has been also known that angiogenesis participates in retinopathy orretinitis. When blood vessel is proliferated in retina, eyesight getsworse and, when progressed, blindness is resulted. Effective therapeuticdrugs have been demanded.

In GB 662798, hydroxy- and acyloxy-phenylsulfonylamino-substitutedquinoline and quinoxaline are disclosed, but relates to antiviral agentsand are different from the present invention. In J. Sci. Ind. Res.,sect. B, 21(1962), 3-p-toluenesulfonylamino-8-hydroxyquinoline isdisclosed. Though, there is no description relating to an antiangiogeniceffect. In JP-A 1-254682, 1,8-naphthylidine and pyrido[2,3-d]pyrimidinederivatives having a substituted sulfonamide are disclosed, but relatesto herbicides and are different from the present invention. In JP-A62-426 and 7-267936, sulfonamidequinoxaline derivatives having antitumoractivity are disclosed. Though, there is no description relating to anantiangiogenic effect.

Accordingly, an object of the present invention is to provide a novelsulfonamide-containing heterocyclic compound that has an excellent anantiangiogenic effect and has a different structure from those ofconventional antiangiogenic agent. Another object of the presentinvention is to provide an intermediate of the compound and apharmaceutical composition containing the compound as an activeingredient.

DISCLOSURE OF THE INVENTION

The present inventors have made intensive investigations for anantiangiogenic agent. As a result, they have found that a novelsulfonamide-containing heterocyclic compound has an excellentantiangiogenic effect and has an excellent effect as a pharmaceuticaldrug. Thus, they have accomplished the present invention.

Specifically, the present invention provides a sulfonamide-containingheterocyclic compound represented by the formula (I), apharmacologically acceptable salt thereof or a hydrate of them.

In the formula:

A is hydrogen atom, a halogen atom, hydroxyl group, a C1-C4 alkyl groupor alkoxy group which may be substituted with a halogen atom, cyanogroup, —(CO)kNR²R³ (wherein, R² and R³ are the same as or different fromeach other and each means hydrogen atom or a C1-C4 alkyl group which maybe substituted with a halogen atom; and k means 0 or 1), a C2-C4 alkenylgroup or alkynyl group which may have a substituent, or a phenyl groupor phenoxy group which may have a substituent selected from thefollowing group A;

B is an aryl group or monocyclic heteroaryl group which may have asubstituent selected from the following group A, or

(wherein, the ring Q is an aromatic ring which may have one or twonitrogen atoms; the ring M is an unsaturated C5-C12 monocyclic orpolycyclic ring which shares a double bond with the ring Q, and the ringmay have 1 to 4 hetero atoms selected from nitrogen atom, oxygen atomand sulfur atom; the ring Q and the ring M may share nitrogen atom witheach other; and the ring Q and the ring M may each have a substituentselected from the following group A);

K is a single bond or —(CR⁴R⁵)m— (wherein, R⁴ and R⁵ are the same as ordifferent from each other and each means hydrogen atom or a C1-C4 alkylgroup; and m is an integer of 1 or 2);

T, W, X and Y are the same as or different from each other and eachmeans ═C(D)— (wherein D is hydrogen atom, a halogen atom, hydroxylgroup, a C1-C4 alkyl group or alkoxy group which may be substituted by ahalogen atom, cyano group, —(CO)nNR⁶R⁷ (wherein R⁶ and R⁷ are the sameas or different from each other and each means hydrogen atom or a C1-C4alkyl group which may be substituted with a halogen atom; and n means 0or 1), or a C2-C4 alkenyl group or alkynyl group which may have asubstituent), or nitrogen atom;

U and V are the same as or different from each other and each means═C(D)— (wherein, D has the same meaning as defined above), nitrogenatom, —CH₂—, oxygen atom or —CO—;

Z is a single bond or —CO—NH—;

R1 is hydrogen atom or a C1-C4 alkyl group; and

means a single or double bond,

Group A

a halogen atom, hydroxyl group, a C1-C4 alkyl group or alkoxy groupwhich may be substituted by a halogen atom, cyano group, —R⁸R⁹N(NH)p—(wherein R⁸ and R⁹ are the same as or different from each other and eachmeans hydrogen atom or a C1-C4 alkyl group which may be substituted witha halogen atom; and p means 0 or 1, and R⁸ and R⁹ may be combined withthe nitrogen atom to which they bound to form a 5- or 6-membered ringwhich may include nitrogen atom, oxygen atom or sulfur atom and may havea substituent), an aminosulfonyl group which may be substituted with oneor two C1-C4 alkyl groups, an optionally substituted C1-C8 acyl group, aC1-C4 alkyl-S(O)s-C1-C4 alkylene group (wherein s means an integer of 0,1 or 2), a phenylsulfonylamino group which may have a C1-C4 alkyl or asubstituent, —(CO)qNR¹⁰R¹¹ (wherein R¹⁰ and R¹¹ are the same as ordifferent from each other and each means hydrogen atom or a C1-C4 alkylgroup which may be substituted with an amino group which may besubstituted with a halogen atom or a C1-C4 alkyl group; and q means 0 or1), or an aryl or heteroaryl group which may have a substituent,

provided that when U is oxygen atom, V means —CO— or —CH₂—; when V isoxygen atom, U means —CO— or —CH₂—; and the following cases 1) whereonly one of T, U, V, W, X and Y is nitrogen atom; and A and D are bothhydrogen atoms, 2) where T, U, V, W, X and Y are all nitrogen atoms, 3)where Y and W are nitrogen atoms; T, U, V and X are ═C(D1)— (wherein D1means hydrogen atom, methyl group, a halogen atom, trifluoromethyl groupor methoxy group); and Z is a single bond; and A is hydrogen atom,methyl group, a halogen atom, trifluoromethyl group or methoxy group, 4)where W is nitrogen atom; T, U, V, X and Y are ═C(D2)— (wherein D2 meanshydrogen atom); K and Z are single bonds; A is hydroxyl group; and B isp-toluenesulfonylamino group, 5) where V and W are nitrogen atoms and 6)where T, V and W are nitrogen atoms are excluded.

The present invention provides a halogen-substituted quinoline compoundrepresented by the following formula:

(wherein, Y₁ and W₁ are different from each other and each meansnitrogen atom or ═C(D³)— (wherein, D³ is hydrogen atom, a halogen atom,hydroxyl group, a C1-C4 alkyl group or alkoxy group which may besubstituted with a halogen atom, cyano group or —(CO)nNR⁶R⁷ (wherein, R⁶and R⁷ are the same as or different from each other and each meanshydrogen atom or a C1-C4 alkyl group which may be substituted with ahalogen atom; and n means 0 or 1)); E is a halogen atom, cyano group ora C1-C4 alkyl group which may be substituted with a halogen atom; J isan amino group which may have a protecting group or a carboxyl groupwhich may have a protecting group; G¹ is hydrogen atom, a halogen atom,hydroxyl group, a C1-C4 alkyl group or alkoxy group which may besubstituted with a halogen atom, cyano group, —(CO)tNR¹⁴R¹⁵ (wherein,R¹⁴ and R¹⁵ are the same as or different from each other and each meanshydrogen atom or a C1-C4 alkyl group which may be substituted with ahalogen atom; and t means 0 or 1), or an optionally substituted C2-C4alkenyl group or alkynyl group which is a production intermediate of thecompound represented by the above formula (I), or a salt thereof.

In addition, the present invention provides a process for producing acompound represented by the formula:

(wherein E¹ is a halogen atom; R¹⁶ is a carboxyl-protecting group; G² ishydrogen atom, a halogen atom, hydroxyl group or a C1-C4 alkyl group oralkoxy group which may be substituted with a halogen atom), whichcomprises the step of reducing a compound represented by the formula:

(wherein E¹ is a halogen atom; E² is chlorine atom or bromine atom; R¹⁶is a carboxyl-protecting group; G² is hydrogen atom, a halogen atom,hydroxyl group, or a C1-C4 alkyl group or alkoxy group which may besubstituted with a halogen atom) with tin, zinc or iron.

The compound represented by the above formula (IV) is a compound of theabove formula (II) wherein Y₁ is nitrogen atom; W₁ is ═CH—; E is ahalogen atom; J is a carboxyl group having a protecting group; and G¹ ishydrogen atom, a halogen atom, hydroxyl group, or a C1-C4 alkyl group oralkoxy group which may be substituted with a halogen atom.

The present invention provides an antiangiogenic agent, an anti-canceragent, a cancer metastasis suppressor, a therapeutic agent for diabeticretinopathy, a therapeutic agent for rheumatic arthritis or atherapeutic agent for hematoma, comprising the sulfonamide-containingheterocyclic compound represented by the above formula (I) apharmacologically acceptable salt thereof or a hydrate of them, as anactive ingredient.

The present invention provides a method for preventing or treating adisease against which an antiangiogenic effect is efficacious for theprevention or treatment of cancer, cancer-metastasis, diabeticretinopathy, rheumatic arthritis or hematoma, by administering apharmacologically effective amount of the sulfonamide-containingheterocyclic compound represented by the above formula (I), apharmacologically acceptable salt thereof or a hydrate of them to apatient.

The present invention provides use of the sulfonamide-containingheterocyclic compound represented by the above formula (I), apharmacologically acceptable salt thereof or a hydrate of them, forproducing an antiangiogenic agent, an anti-cancer agent, a cancermetastasis suppressor, a therapeutic agent for diabetic retinopathy, atherapeutic agent for rheumatic arthritis or a therapeutic agent forhematoma.

In the present invention, the “aromatic ring which may have one or twonitrogen atoms” in ring Q is an aromatic hydrocarbon or a 6-memberedaromatic heterocycle including one or two nitrogen atoms. Examples ofsuch aromatic rings in ring Q are benzene, pyridine, pyrimidine,pyrazine, pyridazine etc. The “unsaturated C5-C12 monocyclic orpolycyclic ring, which may have one to four hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom” as ring M means anunsaturated monocyclic or polycyclic ring which shares a double bondwith ring Q and includes aromatic hydrocarbon rings such as benzene andnaphthalene; unsaturated hydrocarbon rings such as cyclopentene,cyclohexene, cycloheptene, cyclooctene, cyclopentadienes,cycloheptadienes and cyclooctadienes; and unsaturated heterocyclic ringssuch as tetrahydropyridine, pyrrole, furan, thiophene, oxazole,isoxazole, thiazole, isothiazole, pyrazole, imidazole, triazole,pyridine, pyrimidine, pyrazine, pyridazine, triazine, indole, isoindole,quinoline, isoquinoline, indazolidine, naphthylidine, benzofuran,benzopyran, benzothiophene, benzimidazole, benzoxazole, benzothiazole,pyrrolopyridine, pyridopyrimidine and imidazopyridine. The phrase “ringQ and ring M may share one nitrogen atom with each other” means the casewhere the nitrogen atom is present at the condensation position betweenthe two rings, and such rings include, for example, indazolidine,imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine andpyrazolo[1,5-a]pyrimidine.

In the present invention, the C1-C4 alkyl group in R₁, R⁴ and R⁵, andthe C1-C4 alkyl group in the C1-C4 alkyl group which may be substitutedwith a halogen atom in A, D, R₁, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, G¹, G² and Group A include linear or branched alkylgroups having 1 to 4 carbon atoms such as methyl group, ethyl group,n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group and tert-butyl group. The phrase “which may besubstituted with a halogen atom” means that each of these alkyl groupsmay be substituted by a halogen atom(s) selected from fluorine atom,chlorine atom, bromine atom and iodine atom. Such halogen-substitutedalkyl groups include, for example, monofluoromethyl group,monochloromethyl group, difluoromethyl group, trifluoromethyl group, 1-or 2-monofluoroethyl group, 1- or 2-monochloroethyl group, 1- or2-monobromoethyl group, 1,2-difluoroethyl group, 1,2-dichloroethylgroup, 1,1,2,2,2-pentafluoroethyl group and 3,3,3-trifluoropropyl group.Among them, monofluoromethyl group, difluoromethyl group,trifluoromethyl group, 1- or 2-monofluoroethyl group, 1,2-difluoroethylgroup and 1,1,2,2,2-pentafluoroethyl group are preferred.

In the present invention, the C1-C4 alkoxy group in the C1-C4 alkoxygroup which may be substituted with a halogen atom in A, D and Group Aincludes linear or branched alkoxy groups having 1 to 4 carbon atoms,such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group,n-butyloxy group, isobutyloxy group, sec-butyloxy group andtert-butyloxy group. The phrase “which may be substituted with a halogenatom” means that each of these alkoxy groups may be substituted by ahalogen atom(s) selected from fluorine atom, chlorine atom, bromine atomand iodine atom. Such halogen-substituted alkoxy groups include, forexample, monofluoromethoxy group, difluoromethoxy group,trifluoromethoxy group, 1- or 2-monofluoroethoxy group, 1- or2-monochloroethoxy group, 1- or 2-monobromoethoxy group,1,2-difluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group and3,3,3-trifluoropropoxy group. Among them, monofluoromethoxy group,difluoromethoxy group, trifluoromethoxy group, 1- or 2-monofluoroethoxygroup, 1,2-difluoroethoxy group and 1,1,2,2,2-pentafluoroethoxy groupare preferred.

In the present invention, the C2-C4 alkenyl group or alkynyl group in Aand D includes alkenyl groups or alkynyl groups having 2 to 4 carbonatoms, such as vinyl group, allyl group, 2- or 3-butenyl group,1,3-butanedienyl group, ethynyl group, 2-propynyl group, 2-methylethynylgroup, and 2- or 3-butynyl group.

The aryl group in B and Group A in the present invention means andincludes aromatic hydrocarbon groups such as phenyl group and naphthylgroup. The heteroaryl group means and includes monocyclic and polycyclicrings each containing one or more nitrogen atoms, oxygen atoms andsulfur atoms. Such heteroaryl groups include, for example, pyrrolyl,imidazolyl group, pyrazolyl group, triazolyl group, furyl group, thienylgroup, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolylgroup, thiadiazolyl group, pyridyl group, pyrimidyl group, pyrazylgroup, indolyl group, indolizinyl group, benzimidazolyl group,benzothiazolyl group, benzoxazolyl group, quinolinyl group,isoquinolinyl group, quinazolinyl group, and phthalazinyl group.

The phrase “R⁸ and R⁹ may be combined with the nitrogen atom to whichthey bound to form a 5- or 6-membered ring which may include nitrogenatom, oxygen atom or sulfur atom” in R⁸ and R⁹ in the present inventionmeans that R⁸ and R⁹ together with the nitrogen atom to which they boundform a ring such as pyrrolidinyl group, piperidinyl group, morpholinogroup, thiomorpholino group and piperazinyl group.

In the present invention, the C1-C4 alkyl group in the aminosulfonylgroup which may be substituted with one or two C1-C4 alkyl groups, anoptionally substituted C1-C8 acyl group, the C1-C4 alkyl-S(O)s-C1-C4alkylene group, C1-C4 alkyl- or phenyl-sulfonylamino group which phenylgroup may have a substituent and the C1-C4 alkyl group which may besubstituted with an amino group which may be substituted with a halogenatom or a C1-C4 alkyl group in Group A mean and include the same alkylgroups as mentioned above. The alkylene group includes, for example,methylene group, ethylene group, propylene group and butylene group, aswell as methylmethylene group, 1- or 2-methylethylene group, 1-, 2- or3-methylpropylene group and dimethylmethylene group.

The C1-C8 alkanoyl group means, for example, formyl group, acetyl group,propionyl group, butyryl group, isobutyryl group, valeryl group, benzoylgroup etc.

The protecting group in the “amino group which may have a protectinggroup” in J in the present invention is not specifically limited as longas it is generally used as an amino-protecting group in organicsynthesis. Such protecting groups include, but are not limited to,benzyloxycarbonyl group, t-butoxycarbonyl group, formyl group, acetylgroup, chloroacetyl group, 2,2,2-trichloroethyl group, benzylidenegroup, benzhydryl group and trityl group. The protecting group in thecarboxyl group which may have a protecting group and thecarboxy-protecting group in R¹⁶ are not specifically limited and can beany protecting groups as long as they are generally used ascarboxyl-protecting groups in organic synthesis. Such protecting groupsinclude, but are not limited to, methyl group, ethyl group, propylgroup, isopropyl group, t-butyl group, methoxymethyl group,2,2,2-trichloroethyl group, pivaloyloxymethyl group and benzyl group.

In the present invention, the substituent in the phrase “which may havea substituent” means and includes the aforementioned halogen atoms,C1-C4 alkyl groups or alkoxy groups which may be substituted with ahalogen atom, hydroxyl group, hydroxy-C1-C4 alkyl groups, amino groupswhich may be substituted with one or two C1-C4 alkyl groups, C2-C4alkenyl groups or alkynyl groups, cyano group, C1-C8 acyl groups,aminosulfonyl groups which may be substituted with one or two C1-C4alkyl groups, carboxyl group, C1-C4 alkoxy-carbonyl groups, andcarbamoyl groups which may be substituted with one or two C1-C4 alkylgroups.

The sulfonamide-containing heterocyclic compounds represented by theabove formula (I) may form salts with acids or bases. The presentinvention also includes the salts of the compound (I). Such salts withacids include, for example, inorganic acid salts such as hydrochlorate,hydrobromate and sulfate; and salts with an organic acid such as aceticacid, lactic acid, succinic acid, fumaric acid, maleic acid, citricacid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid.Examples of the salt with a base are an inorganic salt such as sodiumsalt, potassium salt and calcium salt, and that with an organic basesuch as triethylamine, arginine or lysine.

It goes without saying that the present invention further includes allthe optical isomers, if any, as well as a hydrate of these compounds.Further, the compounds which show an antiangiogenic effect produced fromthe compound of the present invention by subjecting as a result ofmetabolism such as oxidation, reduction and hydrolysis in vivo are alsoincluded. The present invention further includes the compounds whichproduce the compound of the present invention as a result of metabolismsuch as oxidation, reduction and hydrolysis in vivo.

The compounds (I) of the present invention can be prepared by variousprocesses. Representative processes of them are as follows.

1) When Z is a Single Bond

In the formula, A, B, T, U, V, W, X and T have the same meanings asdefined above.

Specifically, the objective compounds can be prepared by allowing asulfonic acid represented by the formula (V) or a reactive derivativethereof to react with a compound represented by the formula (VI).

Such reactive derivatives of the sulfonic acid (V) include, for example,generally used reactive derivatives such as sulfonyl halides, sulfonylanhydrides and N-sulfonylimidazolide. Among them, sulfonyl halides aretypically preferred. Solvents for use in the reaction are notspecifically limited, but are preferably solvents that dissolve materialsubstances and are inert to these materials. Such solvents includepyridine, tetrahydrofuran, dioxane, benzene, ethyl ether,dichloromethane, dimethylformamide, and mixtures of these solvents. Whenan acid liberates accompanied with a proceeding reaction as in the casewhen a sulfonyl halide is used in the reaction, the reaction ispreferably performed in the presence of an appropriate deacidificationagent. Therefore, in such a case, pyridine and other basic solvents aretypically preferably used. When a neutral solvent is used, an alkalimetal carbonate, an organic tertiary amine or another basic substancemay be added to the reaction system. Solvents that can be used hereinare not limited to those mentioned above. The reaction generallyproceeds at room temperature, but the reaction system may be cooled orheated according to necessity. The reaction time can optionally beselected depending on the types of material compounds and the reactiontemperature and is generally from 10 minutes to 20 hours.

When the amino group or hydroxyl group of the resulting product isprotected, a sulfonamide derivative (VII) having a free hydroxyl groupor amino group can be obtained by subjecting the product to treatmentwith an acid, treatment with a base, catalytic reduction and otherconventional deprotecting procedures according to necessity.

2) When Z is —CO—NH—

In the formula, L is chlorine atom or bromine atom; R¹⁷ is a C1-C4 alkylgroup or a benzyl group; and A, B, T, U, V, W, X and Y have the samemeanings as defined above.

The target compound can be prepared by allowing an isocyanate compoundrepresented by the formula (VIII) to react with sulfonamide compoundrepresented by the formula (IX).

The reaction is generally performed in water or a water-miscible inertsolvent such as tetrahydrofuran and acetone in the presence of a basesuch as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodiummethoxide and sodium hydride. The reaction is performed at a temperaturefrom 0° C. to 100° C. and preferably from about 20° C. to about 30° C.

Alternatively, the target compound is prepared by a process in which thesulfonamide represented by the formula (IX) is allowed to react with ahaloformate represented by the formula (XIII) to give a carbamaterepresented by the formula (XII), and the resulting carbamate is allowedto react with an amine represented by the formula (XI).

The reaction between the sulfonamide represented by the formula (IX) andthe haloformate represented by the formula (XIII) is performed in aninert solvent such as acetone, tetrahydrofuran and methyl ethyl ketonein the presence of an acid scavenger such as potassium carbonate, sodiumcarbonate, potassium hydroxide and sodium hydroxide. A reactiontemperature may range from about 30° C. to reflux temperature.Subsequently, the reaction between the carbamate represented by theformula (XII) and the amine represented by the formula (XI) is performedby heating in an inert high-boiling solvent such as dioxane, toluene anddiglyme at temperatures ranging from about 50° C. to reflux temperature.

The amine compounds represented by the formula (VI) or (XI) arematerials for the sulfonamide- or sulfonylurea-containing heterocycliccompounds of the present invention and can be prepared by combinationsof conventional procedures.

For example, quinoline and isoquinoline derivatives can be preparedaccording to the following production processes.

In the formula, A, E₂, G² and R¹⁶ have the same meanings as definedabove; and R¹⁸ is a C1-C4 alkyl group or a benzyl group.

In the formula, A and G² have the same meanings as defined above.

In the formula, R¹⁸ has the same meaning as defined above; and R¹⁹ is aC1-C4 alkyl group.

In the formula, R¹⁸ and E² have the same meanings as defined above; R²⁰and R²¹ are each hydrogen atom or a C1-C4 alkyl group; R²² is a C1-C4alkoxy group, an optionally substituted phenoxy group or phenyl group,cyano group, or an amino group which may be substituted with one or twoC1-C4 alkyl groups; and E³ is hydrogen atom, a halogen atom, a C1-C4alkoxy group, an optionally substituted phenoxy group or phenyl group,cyano group, or an amino group which may be substituted with one or twoC1-C4 alkyl groups.

When the compounds of the present invention are used as pharmaceuticaldrugs, they are administered to a patient orally or parentally. The dosevaries depending on the severity of symptoms, age, sex, body weight andsensitivity of the patient, medication method, administration timeperiod, administration interval, characteristics, dispensing and type ofthe resulting pharmaceutical preparation, the type of the activeingredient etc., and is not specifically limited. The dose is generallyfrom 10 to 6000 mg, preferably from about 50 to about 4000 mg and morepreferably from 100 to 3000 mg per day per adult. The drug isadministered to a subject one to three times a day.

To prepare oral solid preparations, fillers and, where necessary, otheradditives such as binders, disintegrators, lubricants, coloring agentsand flavoring agents are added to a base component, and the resultingmixture is formed into tablets, coated tablets, granules, fine granules,powders, capsules etc. according to a conventional procedure.

Such fillers include lactose, corn starch, sucrose, glucose, sorbitol,crystalline cellulose and silicon dioxide. The binders include, forexample, polyvinyl alcohol, ethyl cellulose, methylcellulose, gumarabic, hydroxypropylcellulose and hydroxypropylmethylcellulose. Thelubricants include magnesium stearate, talc and silica. The coloringagents include those permitted to use in pharmaceutical drugs. Theflavoring agents include cocoa powder, menthol, aromatic powder,peppermint oil, borneol and powdered cinnamon bark. These tablets andgranules can be coated with sugar, gelatin or other coating substancesaccording to necessity.

To prepare injections, additives such as pH adjusting agents, buffers,suspending agents, solubilizing agents, stabilizers, isotonicity andpreservatives are added to the base component, and the resulting mixtureis formed into intravenous injections, subcutaneous injections orintramuscular injections according to a conventional procedure. Wherenecessary, the injections are formed into freeze-dried preparations.

Such suspending agents include methylcellulose, polysorbate 80,hydroxyethylcellulose, gum arabic, powdered tragacanth, sodiumcarboxymethylcellulose and polyoxyethylene sorbitan monolaurate.

The solubilizing agents include polyoxyethylene hydrogenated caster oil,polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate,Macrogol and caster oil fatty acid ethyl esters.

The stabilizers include sodium sulfite and sodium metasulfite, and thepreservatives include, for example, methyl parahydroxybenzoate, ethylparahydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.

The effect of the compounds of the present invention will be illustratedwith reference to Pharmacological Experimental Example below.

Pharmacological Experimental Example 1, Antiangiogenic Effect

The inhibition degree of angiogenesis which was observed when aortapieces of rat were incubated in collagen was defined as anantiangiogenic effect. That is, the thoracic aorta excised from male ratof Sprague-Dawley strain (10-12 weeks age) was washed with a Hanks'solution (Gibco BRL, Gaithersburg, USA) so that fat tissues around therewere removed minutely. The aorta was incised to prepare pieces of 2 mmsquare and they were allowed to stand in a 24-well plate holding theendothelial cells upside. Then, 500 μl of neutralized Type I collagen(Cell Matrix Type I-A; manufactured by Nitta Gelatin) were poured overeach well and allowed to stand at room temperature for about 20 minutesin a clean bench to solidify the gel. After confirming that the gel wassolidified, 500 μl of MCDB 131 medium (manufactured by Chlorella Kogyo)were added thereto followed by incubating in a CO₂ incubator (5% CO₂) at37° C. On the next day, the culture medium was exchanged with 500 μl ofMCDB 131 medium containing the test compound and the incubation wascontinued. After three days, the medium was again exchanged with 500 μlof MCDB 131 medium containing the test compound and, at the stage of the7th day from the initiation of addition of the test compound, numbers ofcapillaries formed around the aorta were counted under a microscope. Thesolution containing the test compound was prepared in a three-folddilution system where 10 μg/ml was the highest concentration.

Inhibiting rate was calculated from the following formula and 50%inhibiting concentration (IC₅₀) for each test compound was determined.

Inhibiting Rate (%)=(C−T)/C_(x)100

C: Numbers of capillaries when no compound was added

T: Numbers of capillaries when a compound was added Table 1

Test Compound (Ex. No.) IC₅₀ (μg/ml) Ex 1 0.49 Ex 2 0.74 Ex 4 0.09 Ex 60.12 Ex 11 0.04 Ex 15 0.87 Ex 24 0.49 Ex 27 0.08 Ex 38 0.15 Ex 47 0.09Ex 48 0.35 Ex 50 0.31 Ex 53 0.53 Ex 59 0.20 Ex 61 0.3 Ex 69 0.15 Ex 770.39 Ex 80 0.20 Ex 81 0.85 Ex 84 0.14 Ex 91 0.33 Ex 92 0.2

EXAMPLES

Next, Preparation Examples illustrating the preparation of materialcompounds for the compounds of the present invention and Examples ontypical examples of the compounds of the present invention are shownbelow. Though these Examples are not intended to limit the scope of thepresent invention.

Preparation Example 1

2-Amino-9-bromoquinoline

After stirring 2-bromo-6-nitrobenzaldehyde (30.4 g), magnesium oxide (75g) and dimethyl sulfoxide (11.3 ml) sufficiently for 1 minute, diethyl(cyanomethyl)phosphonate (25.8 ml) was added thereto and the mixture wasstirred for further 2 hours. After the completion of stirring, themixture was left stand overnight. Then, ethyl acetate was added thereto,and the mixture was stirred and then filtered. The filtrate wasconcentrated and the residue was purified by silica gel columnchromatography (ethyl acetate), to give 32 g of3-(2-bromo-6-nitrophenyl)-2-propenenitrile (E-isomer:Z-isomer=3:1).

¹H-NMR(CDCl₃) δ (ppm): 5.63(d, J=16.5 Hz, E-isomer 1H), 5.81(d, J=10.8Hz, Z-isomer 1H), 7.42-7.52(m, E-isomer 1H, Z-isomer 2H), 7.56(d, J=16.5Hz, E-isomer 1H), 7.90-8.16(m, E-isomer 2H, Z-isomer 2H).

Next, ethanol (250 ml), tin (60 g) and distilled water (150 ml) wereadded to 32 g of 3-(2-bromo-6-nitrophenyl)-2-propenenitrile(E-isomer:Z-isomer=3:1), the resulting mixture was heated to 90° C.under stirring, followed by dropwise addition of concentratedhydrochloric acid (256 ml) and stirring at 90° C. for 3 hours. Aftercooling to room temperature, the liquid layer was separated bydecantation and cooled to 0° C. The resulting solid matter was collectedby filtration, was diluted with aqueous ammonia and was extracted withethyl acetate. The extract was concentrated and the residue was purifiedby silica gel column chromatography (ethyl acetate), to give 5.0 g ofthe title compound.

¹H-NMR(CDCl₃) δ (ppm): 4.88(2H, bs), 6.79(1H, d, J=9.3 Hz), 7.39(1H, t,J=8.9 Hz), 7.51(1H, d, J=8.9 Hz), 7.61(1H, d, J=8.9 Hz), 8.27(1H, d,J=9.3 Hz).

Preparation Example 2

2-Amino-5-chloroquinoline

The title compound was obtained from 2-chloro-6-nitrobenzaldehyde in thesame manner as in Preparation Example 1.

¹H-NMR(CDCl₃) δ (ppm): 5.25(2H, bs), 6.80(1H, d, J=9.7 Hz), 7.32(1H, dd,J=7.5 Hz, 1.5 Hz), 7.46(1H, t, J=7.5 Hz), 7.57(1H, m), 8.30(1H, d, J=9.7Hz, 1.0 Hz).

Preparation Example 3

3-Carbethoxy-4-hydroxy-8-bromoquinoline

A mixture of 50 g (0.291 mol) of 2-bromoaniline and 63 g (0.291 mol) ofdiethyl ethoxymethylenemalonate was heated at 100° C. under a reducedpressure for 3 hours, followed by heating at 200° C. for further 12hours. After the completion of the reaction, the solid matter in theresulting reaction mixture was washed with ethyl acetate, and thecrystals were collected by filtration and dried, to give 50 g of thetitle compound.

¹H-NMR(DMSO-d₆) δ (ppm): 1.26(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz),7.34(1H, t, J=7.6 Hz), 8.03(1H, dd, J=1.6 Hz, 7.6 Hz), 8.15(1H, dd,J=1.6 Hz, 7.6 Hz), 8.43(1H, s), 11.56(1H, s).

Preparation Example 4

3-Carbethoxy-8-bromoquinoline

A mixture of 2.5 g (8.4 mmol) of 3-carbethoxy-4-hydroxy-8-bromoquinolineand 10 ml of phosphorus oxychloride was heated under reflux for 1 hour.After the completion of the reaction, phosphorus oxychloride was removedand the residue was purified by NH silica gel, to give 2.6 g of achlorinated derivative. Next, 500 mg (1.6 mmol) of the chlorinatedderivative was dissolved in 20 ml of dioxane, and 1 g of powdered zincand 3 ml of acetic acid were added thereto, followed by heating at 65°C. for 30 minutes. To the reaction mixture was added ethyl acetate,followed by filtering through Celite. The filtrate was washed withbrine, dried over magnesium sulfate and concentrated. To the residue wasadded 1 ml of acetic acid, and the mixture was left stand for 12 hours.Then, acetic acid was removed, and the residue was subjected to silicagel column chromatography and eluted with an eluent (ethylacetate-n-hexane=1-7), to give 180 mg of the title compound.

¹H-NMR(CDCl₃) δ (ppm): 1.47(3H, t, J17.2 Hz), 4.50(2H, q, J=7.2 Hz),7.50(1H, t, J=7.6 Hz), 7.93(1H, dd, J=1.2 Hz, 7.6 Hz), 8.18(1H, dd,J=1.2 Hz, 7.6 Hz), 8.85(1H, d, J=2 Hz), 9.57(1H, d, J=2 Hz).

Preparation Example 5

3-Amino-8-bromoquinoline

To a mixture of ethanol (10 ml) and 1 N NaOH aqueous solution (10 ml)was added 500 mg (1.8 mmol) of 3-carbethoxy-8-bromoquinoline, followedby stirring at room temperature for 3 hours. Ethanol was removed, andthe residue was neutralized with 1 N HCl. The resulting solid wascollected by filtration, washed with water and dried, to give 450 mg ofa carboxylic acid. Then, 450 mg (1.8 mmol) of the carboxylic acid wasadded to 25 ml of tert-butanol, and 0.58 ml (2.7 mmol) of DPPA and 0.37ml (2.7 mmol) of triethylamine were further added thereto, followed byheating under reflux for 12 hours. The reaction mixture wasconcentrated, and the residue was subjected to silica gel chromatographyand eluted with an eluent (ethyl acetate-n-hexane=1-4), to give 352 mgof an amide derivative. Then, 350 mg (1.1 mmol) of the amide derivativewas added to a mixture of 4 ml of methanol and 2 ml of concentrated HCl,followed by stirring at room temperature for 1 hour. The reactionmixture was basified with aqueous ammonia and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate and then concentrated, to give 240 mg of the title compound.

¹H-NMR(DMSO-d₆) δ (ppm): 5.88(2H, s), 7.13(1H, d, J=2.8 Hz), 7.24(1H, ddJ=7.6 Hz, 8.4 Hz), 7.59-7.65(2H, m), 8.49(1H, d, J=2.8 Hz).

Preparation Example 6

3-Amino-8-iodoquinoline

The title compound was obtained from 2-iodoaniline in the same manner asin Preparation Examples 3 to 5.

¹H-NMR(DMSO-d₆) δ (ppm): 5.85(2H, s), 7.07(1H, d, J=2.8 Hz), 7.10(1H, t,J=7.6 Hz), 7.62(1H, dd, J=1.2 Hz, 7.6 Hz), 7.90(1H, dd, J=1.2 Hz, 7.6Hz), 8.45(1H, dd, J=2.8 Hz).

Preparation Example 7

3-Amino-8-cyanoquinoline

The title compound was obtained from 2-cyanoaniline in the same manneras in Preparation Examples 3 to 5.

¹H-NMR(DMSO-d₆) δ (ppm): 6.03(2H, br s), 7.22(1H, d, J=2.8 Hz), 7.48(1H,dd, J=7.2 Hz, 8.4 Hz), 7.84(1H, dd, J=1.2 Hz, 8.4 Hz), 7.94(1H, dd,J=1.2 Hz, 8.4 Hz), 8.57(1H, d, J=2.8 Hz).

Preparation Example 8

3-Amino-8-(methylsulfonyl) quinoline

The title compound was obtained in the same manner as in PreparationExamples 3 to 5.

¹H-NMR(CDCl₃) δ (ppm): 6.00(2H, s), 7.26(1H, d, J=2.4 Hz), 7.53(1H, t,J=7.2 Hz), 7.91(1H, dd, J=1.6 Hz, 7.2 Hz), 7.96(1H, dd, J=1.2 Hz, 8.4Hz), 8.58(1H, d, J=2.8 Hz).

Preparation Example 9

3-Amino-8-chloroquinoline

The title compound was obtained in the same manner as in PreparationExamples 3 to 5.

¹H-NMR(DMSO-d₆) δ (ppm): 5.90(2H, s), 7.17(1H, d, J=2.8 Hz), 7.33(1H, t,J=7.6 Hz), 7.46(1H, d, J=7.6 Hz), 7.58(1H, d, J=7.6 Hz), 8.52(1H, d,J=2.8 Hz).

Preparation Example 10

3-Amino-8-trifluoromethylquinoline

The title compound was obtained in the same manner as in PreparationExamples 3 to 5.

¹H-NMR(DMSO-d₆) δ (ppm): 5.94(2H, s), 7.23(1H, d, J=2.8 Hz), 7.48(1H, t,J=7.6 Hz), 7.69(1H, d, J=7.6 Hz), 7.91(1H, d, J=7.6 Hz), 8.55(1H, d,J=2.8 Hz).

Preparation Example 11

Ethyl 8-Chloro-4-vinylquinoline-3-carboxylate

To a solution of 2.0 g (7.4 mmol) of ethyl4,8-dichloroquinoline-3-carboxylate obtained in the same manner as inPreparation Example 4 in toluene (20 ml) were added tributylvinyltin(2.8 ml) and tetrakis(triphenylphosphine)palladium (171 mg), followed bystirring for 2 hours while heating under reflux. The reaction mixturewas filtrated through Celite and concentrated. Then, the residue waspurified by silica gel chromatography, to give 1.92 g of the titlecompound.

¹H-NMR(DMSO-d₆) δ (ppm): 1.36(3H, t, J=7.6 Hz), 4.37(2H, d, J=7.6 Hz),5.52(1H, d, J=18.0 Hz), 5.58(1H, d, J=16.4 Hz), 7.40(1H, dd, J=16.4,18.0 Hz), 7.70(1H, t, J=8.0 Hz), 8.11(1H, d, J=8.0 Hz), 8.25(1H, d,J=8.0 Hz), 9.24(1H, s).

Preparation Example 12

3-Amino-8-chloro-4-vinylquinoline

The title compound was obtained from ethyl4-vinyl-8-chloroquinoline-3-carboxylate in the same manner as inPreparation Example 5.

¹H-NMR(DMSO-d₆) δ (ppm): 5.69(1H, dd, J=1.6, 18.0 Hz), 5.81(2H, s),5.84(1H, dd, J=1.6, 11.6 Hz), 6.91(1H, dd, J=11.6, 18.0 Hz), 7.38(1H, t,J=8.0 Hz), 7.52(1H, dd, J=1.2, 8.0 Hz), 7.85(1H, dd, J=1.2, 8.0 Hz),8.60(1H, s).

Preparation Example 13

Ethyl 7-Amino-2-chloroquinoline-4-carboxylate

To 25 g (231 mmol) of m-phenylenediamine was added 43 g (231 mmol) ofdiethyl oxaloacetate, followed by stirring at 160 degrees for 1 hour.After standing to cool, the crystals were washed with methanol. To asolution of the crystals (3.0 g, 13 mmol) in chloroform (30 ml) wasadded phosphorus oxychloride (3.6 ml), followed by heating under refluxfor 1 hour. After standing to cool, the reaction mixture was poured ontoice water, basified with 1 N sodium hydroxide aqueous solution, and theresulting crystals were collected by filtration. The crystals werewashed with tetrahydrofuran and the filtrate was evaporated, to give4.85 g of the title compound.

¹H-NMR(DMSO-d₆) δ (ppm): 1.31-1.42(3H, m), 4.34-4.46(2H, m), 6.92(1H, d,J=2.4 Hz), 7.12(1H, dd, J=2.4, 9.2 Hz), 7.40(1H, s), 8.21(1H, d, J=9.2Hz).

Preparation Example 14

2-Benzylthio-4-methoxypyridazine

In dimethyl sulfoxide (30 ml) was suspended 843 mg (21 mmol, 55% in oil)of sodium hydroxide, and 2.0 ml (16.7 mol) of benzylmercaptan was addedthereto under ice-cooling, followed by stirring for 10 minutes. To thereaction mixture was added 2.5 g (17.6 mmol) of4-methoxy-2-chloropyridazine, followed by stirring at room temperatureovernight. To the reaction mixture was added an aqueous saturatedammonium chloride, followed by extracting with ethyl acetate. Theorganic layer was washed with brine, dried over magnesium sulfate andconcentrated. Then, the residue was purified by silica gelchromatography, to give 1.63 g of the title compound.

¹H-NMR(DMSO-d₆) δ (ppm): 3.98(3H, s), 4.48(2H, s), 7.12(1H, d, J=8.8 Hz)7.22-7.26(1H, m), 7.29-7.37(2H, m), 7.41-7.44(2H, m), 7.57(1H, d, J=8.8Hz).

Preparation Example 15

2-Benzylthio-4-carboxamidepyridine

To 25 g (159 mmol) of 2-chloroisonicotinic acid was added thionylchloride (120 ml), followed by stirring for 3 hours while heating underreflux. After standing to cool, the reaction mixture was evaporated, togive the residue. A solution of the residue in tetrahydrofuran (200 ml)was poured into a mixed solution of a saturated ammonium aqueoussolution (200 ml) and tetrahydrofuran solution (200 ml) underice-cooling. After stirring for 15 minutes while ice-cooling, themixture was evaporated, and the resulting crystals were collected byfiltration and washed with water, to give 22.6 g of white crystals. To asolution of 5.13 g (32 mmol) of the above-prepared white crystals indimethylformamide (70 ml) containing were added 4.2 ml (36 mmol) ofbenzylthiomercaptan and 10 g (77 mmol) of potassium carbonate wereadded, followed by stirring for 3 hours while heating under reflux. Tothe reaction mixture was added water, followed by extracting with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate and evaporated. Then, the residue was purified by silica gelchromatography. The resulting crystals were washed with hexane, to give6.3 g of the title compound.

¹H-NMR(DMSO-d₆) δ (ppm): 4.46(2H, s), 7.22-7.33(3H, m), 7.41(2H, d,J=7.2 Hz), 7.49(1H, dd, J=1.6, 5.2 Hz), 7.67(1H, s), 7.73(1H, s),8.21(1H, s), 8.58(1H, d, J=5.2 Hz).

Preparation Example 16

7-Amino-2-chloro-4-methylquinoline

To 27 g (251 mmol) of m-phenylenediamine was added 32 ml (251 mmol) ofethyl acetoacetate, followed by stirring at 200 degrees for 1 hour.After standing to cool, the crystals were washed with hexane. To 9.5 g(54 mmol) of the crystals was added 15 ml of phosphorus oxychloride,followed by heating under reflux for 2 hours. After standing to cool,the reaction mixture was poured onto ice-water and basified with asaturated ammonium aqueous solution. The resulting crystals werecollected by filtration and washed with water. The crystals were washedwith methanol and the filtrate was evaporated, to give 4.85 g of thetitle compound.

¹H-NMR(DMSO-d₆) δ (ppm): 3.18(3H, s), 5.95(2H, s), 6.82(1H, d, J=2.4 Hz)6.98(1H, s), 7.01(1H, dd, J=2.4, 8.8 Hz), 7.76(1H, d, J=8.8 Hz).

Preparation Example 17

3,4-Dihydroisoquinoline

To a solution of 26.67 g (0.2 mol) of 1,2,3,4-tetrahydroisoquinoline inmethylene chloride (300 ml) was added N-bromosuccinimide (39.2 g) underice-cooling over 20 minutes. After stirring for 40 minutes, 30% sodiumhydroxide aqueous solution (130 ml) was added to the reaction mixture.The organic layer was washed with water, extracted with 10% hydrochloricacid (200 ml), and the aqueous layer was washed with methylene chloride.The aqueous layer was basified with an aqueous ammonia, extracted withmethylene chloride. The extract was dried over magnesium sulfate andthen evaporated. The resulting residue was distilled (about 16 mm-Hg,120 degrees), to give 21.5 g of the title compound as an oil.

¹H-NMR(DMSO-d₆) δ (ppm): 2.66(2H, t, J=8 Hz), 3.62(2H, td, J=2 Hz, 8Hz), 7.19-7.21(1H, m), 7.29-7.33(1H, m), 7.35-7.40(1H, m), 8.31 (1H, t,J=2 Hz).

Preparation Example 18

7-Nitroisoquinoline

To concentrated sulfuric acid (70 ml) was added 15 g of potassiumnitrate, followed by adding a solution of 18 g (0.14 mol) of3,4-dihydroisoquinoline in concentrated sulfuric acid (70 ml) at −15degrees over 20 minutes. After stirring at room temperature for 1 hour,the mixture was heated at 60 degrees for 40 minutes. The reactionmixture was poured onto ice water, and the mixture was basified withaqueous ammonia and extracted with ethyl acetate. The organic layer waswashed with brine, dried over magnesium sulfate and concentrated. To theresidue were added decalin (100 ml), nitrobenzene (100 ml) and Pd-Black(2 g), followed by heating at 200 degrees in a stream of nitrogenovernight. The reaction mixture was washed with ethyl acetate andextracted with 2 N hydrochloric acid. The aqueous layer was washed withethyl acetate, followed by adding an aqueous sodium hydroxide. Theresulting precipitates were collected by filtration and washed withwater, to give 14.4 g of the title compound.

¹H-NMR(CDCl₃) δ (ppm): 7.79(1H, d, J=5.6 Hz), 8.00(1H, d, J=9.2 Hz),8.48(1H, dd, J=2.4 Hz, 9.2 Hz), 8.75(1H, d, J=5.6 Hz), 8.96(1H, d, J=2Hz), 9.48(1H, s).

Preparation Example 19

4-Bromo-7-nitroisoquinoline

To 1.6 g (9.19 mmol) of 7-nitroquinoline were added 1.2 ml of an aqueoushydrobromic acid and 3 ml of bromine, followed by heating at 180 degreesfor 5.5 hours. The reaction mixture was extracted with ethyl acetate,and the extract was successively washed with sodium hydroxide aqueoussolution, sodium thiosulfate aqueous solution and brine, dried overmagnesium sulfate and concentrated. Then, the resulting residue waspurified by silica gel column chromatography (eluted withhexane-hexane:ethyl acetate=4:1), to give 500 mg of the title compound.

¹H-NMR(CDCl₃) δ (ppm): 8.36(1H, d, J=9.2 Hz), 8.58(1H, d, J=2.4 Hz, 9.2Hz), 8.93(1H, s), 8.96(1H, d, J=3.2 Hz), 9.38(1H, s).

Preparation Example 20

7-Amino-4-bromoisoquinoline

In 1 ml of ethanol, 2 ml of tetrahydrofuran and 1 ml of water wasdissolved 66 mg (0.26 mmol) of 7-nitro-4-bromoisoquinoline, and 70 mg ofpowdered iron and 140 mg of ammonium chloride were added thereto,followed by heating at 50 degrees for 3 hours. To the reaction mixturewas added 1 N sodium chloride aqueous solution, followed by extractingwith chloroform. The organic layer was dried over magnesium sulfate andconcentrated. Then, the resulting residue was crystallized fromisopropyl ether, to give 33 mg of the title compound.

¹H-NMR(DMSO-d₆) δ (ppm): 5.98(2H, s), 6.97(1H, d, J=2.4 Hz), 7.31(1H,dd, J=2.4 Hz, 8.8 Hz), 8.28(1H, s), 8.89(1H, s).

Preparation Example 21

6-(4-Toluenesulfonylamino)isoquinoline

In pyridine (30 ml) was dissolved 6-aminoisoquinoline (3.348 g,Synthesis, 733 (1975), and 4-toluenesulfonyl chloride (5.13 g) was addedthereto, followed by stirring at room temperature overnight. Water wasadded thereto, followed by extracting with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated. The residue was recrystallized from ethanol, togive the title compound (5.958 g, 85%) as pale yellow crystals.

¹H-NMR(DMSO-d₆) δ (ppm): 2.28(3H, s), 7.32(2H, d, J=8.2 Hz), 7.40(1H,dd, J=1.6, 9.2 Hz), 7.55(1H, brs), 7.67(1H, d, J=5.6 Hz), 7.74(2H, d,J=8.2 Hz), 7.97(1H, d, J=9.2 Hz), 8.36(1H, d, J=5.6 Hz), 9.10(1H, s).

Preparation Example 22

1-Chloro-6-(4-toluensulfonylamino)isoquinoline

In chloroform (100 ml) was dissolved 3.0 g of6-(4-toluenesulfonylamino)isoquinoline (Preparation Example 21), andm-chloroperbenzoic acid (2.57 g) was added thereto under ice-cooling,followed by stirring at room temperature overnight. The solvent wasevaporated, and the resulting crystals were washed with diethyl ether,collected by filtration and dried, to give pale yellow crystals. Theobtained crystals were suspended in chloroform (83 ml), and phosphorusoxychloride (19 ml) was added thereto, followed by heating under refluxfor 5 hours. After cooling, the solvent was evaporated, and the residuewas basified with an aquesou sodium bicarbonate in an ice-bath, followedby extracting with ethyl acetate, The extract was washed with brine,dried over anhydrous magnesium sulfate and the solvent was evaporated.The residue was purified by silica gel column, to give crude crystals ofthe title compound (1.630 g, 49.40%). The crude crysatals wererecrystallized from ethanol, to give the title compound as colorlesscrystals.

¹H-NMR(DMSO-d₆) δ (ppm): 2.29(3H, s), 7.34(2H, d, J=8.0 Hz), 7.52(1H,dd, J=2.0, 9.0 Hz), 7.65(1H, d, J=2.0 Hz), 7.76(1H, d, J=5.6 Hz),7.77(2H, d, J=8.0 Hz), 8.14(1H, d, J=9.0 Hz), 8.16(1H, d, J=5.6 Hz).

Preparation Example 23

6-Amino -1-chloroisoquinoline

In sulfuric acid (30 ml) was dissolved 3.323 g of1-chloro-6-(4-toluenesulfonylamino)isoquinoline (Preparation Example22), followed by stirring at room temperature overnight. The reactionmixture was poured onto ice, and basified by adding an aqueous sodiumhydroxide and then potassium carbonate, followed by extracting withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated, to give the titlecompound (1.37 g, 76.81%) as yellowish brown crystals.

¹H-NMR(DMSO-d₆) δ (ppm): 6.23(2H, brs), 6.76(1H, s), 7.09(1H, d, J=9.6Hz), 7.37(1H, d, J=6.4 Hz), 7.89(1H, d, J=9.6 Hz), 7.90(1H, d, J=6.4Hz).

Preparation Example 24

2-Chloro-1,6-naphthylidine

In phosphorus oxychloride (19 ml) was dissolved 1.0 g of1,6-naphthyridin-2-one (J. Org. Chem. 4744 (1990), followed by heatingunder reflux at 120° C. for 2 hours. After cooling, the solvent wasevaporated, the residue was basified with water and potassium carbonate,and then the mixture was extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated, to give the title compound (0.658 g, 58.45%) asorange crystals.

¹H-NMR(CDCl₃) δ (ppm): 7.55(1H, d, J=8.8 Hz), 7.86(1H, d, J=6.0 Hz),8.28(1H, d, J=8.8 Hz), 8.80(1H, d, J=6.0 Hz), 9.29(1H, s).

Preparation Example 25

2-Amino-1,6-naphthylidine

In a sealed tube, 2-chloro-1,6-naphthylidine (0.628 g, PreparationExample 22) and aqueous ammonia (40 ml) were heated at 130° C. for 11hours. After cooling, the reaction mixture was extracted with ethylacetate, and the extract was washed with brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated. The residue waspurified by silica gel column, to give the title compound (0.497 g,89.73%) as pale yellow crystals.

¹H-NMR(DMSO-d₆) δ (ppm): 6.81(1H, d, J=8.8 Hz), 7.24(1H, d, J=5.8 Hz),7.97(1H, d, J=8.8 Hz), 8.34(1H, d, J=5.8 Hz), 8.80(1H, s).

Preparation Example 26

N-(3-nitrophenethyl)phthalimide

In tetrahydrofuran (225 ml) was dissolved 15 g of 3-nitrophenethylalcohol, followed by adding triphenylphosphine (26 g) and phthalimide(13.9 g). Then, the resulting mixture was ice-cooled, followed bydropwise addition of diethyl azodicarboxylate (15.5 ml). After stirringat room temperature for 1 hour, the resulting crystals were collected byfiltration, washed with diethyl ether and dried, to giveN-(3-nitrophenethyl)phthalimide as colorless crystals.

¹H-NMR(CDCl₃) δ (ppm): 3.12(2H, t, J=7.4 Hz), 3.98(2H, t, J=7.4 Hz),7.47(1H, dd, J=8.0, 8.0 Hz), 7.60(1H, d, J=8.0 Hz), 7.72(2H, m),7.83(2H, m), 8.09(1H, d, J=8.0 Hz), 8.12(1H, s).

Preparation Example 27

3-Nitrophenethylamine

In ethanol (150 ml) was suspended N-(3-nitrophenethyl)phthalimideobtained in Preparation Example 26. To the mixture was added hydrazine(5.7 ml), followed by heating under reflux for 1 hour. Though thereaction mixture was once completely dissolved, crystals againprecipitated. The crystals were filtered off and washed with cooledethanol. Then, the solvent was evaporated, to give the title compound(5.559 g, 99%) as a yellow oil.

¹H-NMR(CDCl₃) δ (ppm): 2.87(2H, t, J=6.8 Hz), 3.04(2H, t, J=6.8 Hz),7.48(1H, dd, J=7.6, 8.4 Hz), 7.55(1H, ddd, J=1.2, 1.6, 7.6 Hz), 8.08(2H,m).

Preparation Example 28

N-Acetyl-N-(3-nitrophenethyl)amine

In pyridine (33 ml) was dissolved 5.559 g of 3-nitrophenethylamine(Preparation Example 25), followed by dropwise addition of acetylchloride (2.5 ml) under ice-cooling. After stirring at room temperaturefor 0.5 hour, the mixture was again ice-cooled. Water was added thereto,followed by extracting with ethyl acetate, The extract was washed withbrine, dried over anhydrous magnesium sulfate and the solvent wasevaporated, to give the title compound (6.323 g, 91%) as a yellow oil.

¹H-NMR(CDCl₃) δ (ppm): 1.97(3H, s), 2.95(2H, t, J=7.0 Hz), 3.55(2H, dt,J=6.0, 7.0 Hz), 5.60(1H, brs), 7.49(1H, dd, J=7.2, 8.0 Hz), 7.55(1H, d,J=7.2 Hz), 8.07(1H, s), 8.12(1H, d, J=8.0 Hz).

Preparation Example 29

N-Acetyl-N-(3-aminophenethyl)amine

In ethanol (40 ml) was dissolved 2.1 g ofN-acetyl-N-(3-nitrophenethyl)amine (Preparation Example 28), andpowdered iron (2.25 g), ammonium acetate (4.3 g) and water (20 ml) wereadded thereto, followed by heating under reflux for 1.5 hours. The solidmatter was filtered off and washed with ethanol, and a part of thefiltrate was evaporated. The residue was extracted with ethyl acetate,washed with brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated, to give the title compound (1.723 g, 96%) as ayellow oil.

¹H-NMR(CDCl₃) δ (ppm): 1.94(3H, s), 2.72(2H, t, J=6.8 Hz), 3.50(2H, dt,J=6.0, 6.8 Hz), 6.53(1H, s), 6.57(1H, d, J=8.0 Hz), 6.59(1H, d, J=7.2Hz), 7.10(1H, dd, J=7.2, 8.0 Hz).

Preparation Example 30

N-Acetyl-N-(3-ethoxycarbonylaminophenethyl)amine

In pyridine (5 ml) was dissolved 1.7 g ofN-acetyl-N-(3-aminophenethyl)amine (Preparation Example 29), followed bydropwise addition of ethyl chloroformate (1.4 ml) under ice-cooling.After stirring at room temperature for 1 hour, the mixture wasice-cooled again. Water was added thereto, followed by extracting withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated, to give the titlecompound (2.358 g, 97%) as a yellow oil.

¹H-NMR(CDCl₃) δ (ppm): 1.29(3H, t, J=7.2 Hz), 1.93(3H, s), 2.76(2H, t,J=7.0 Hz), 3.47(2H, dt, J16.0, 7.0 Hz), 4.20(2H, q, J=7.2 Hz), 5.57(1H,brs), 6.86(1H, d, J=7.2 Hz), 7.21(1H, dd, J=7.2, 8.0 Hz), 7.28(1H, d,J=8.0 Hz), 7.29(1H, s).

Preparation Example 31

6-Ethoxycarbonylamino-1-methyl-3,4-dihydroisoquinoline

Using 1.0 g of N-acetyl-N-(3-ethoxycarbonylaminophenethyl)amine(Preparation Example 30), cyclization reaction was conducted accordingto the procedure described in Heterocycles 31(2), 341 (1990). After thecompletion of the reaction, the reaction mixture was poured onto ice,the mixture was basified with potassium carbonate, and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated, to give the titlecompound as brown oil.

¹H-NMR(CDCl₃) δ (ppm): 1.19(3H, t, J=7.2 Hz), 2.23(3H, s), 2.60(2H, t,J=7.4 Hz), 3.55(2H, t, J=7.4 Hz), 4.13(2H, q, J=7.2 Hz), 7.31(1H, d,J=6.8 Hz), 7.32(1H, s), 7.34(1H, d, J=6.8 Hz).

Preparation Example 32

6-Ethoxycarbonylamino-1-methylisoquinoline

To 6-ethoxycarbonylamino-1-methyl-3,4-dihydroisoquinoline were addedp-cymene (100 ml) and palladium-carbon (0.9 g), followed by heatingunder stirring at 195° C. in nitrogen atmosphere for 1 hour. Afterfiltering off the catalyst, the reaction mixture was washed with ethanoland a part of the filtrate was evaporated. The residue was extractedwith 1N hydrochloric acid, and then basified with potassium carbonate,followed by extracting with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and the solvent wasevaporated, to give the title compound (0.629 g, 69%, 2 steps) as paleyellow crystals.

¹H-NMR(CDCl₃) δ (ppm): 1.30(3H, t, J=7.2 Hz), 2.89(3H, s), 4.26(2H, q,J=7.2 Hz), 7.40(1H, d, J=5.8 Hz), 7.56(1H, dd, J=1.6, 8.8 Hz), 7.99(1H,d, J=8.8 Hz), 8.05(1H, d, J=1.6 Hz), 8.30(1H, d, J=5.6 Hz), 8.37(1H, s).

Preparation Example 33

6-Amino-1-methylisoquinoline

In ethanol (20 ml) was dissolved 0.629 g of6-ethoxycarbonylamino-1-methylisoquinoline (Preparation Example 32), and8 N sodium hydroxide aqueous solution (6.8 ml), followed by heatingunder reflux for 1.5 hours. After cooling as it was to room temperature,an aqueous saturated ammonium chloride was added thereto, followed byextracting with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and the solvent was evaporated, to givethe title compound (0.311 g, 72%) as pale yellow crystals.

¹H-NMR(CDCl₃) δ (ppm): 2.81(3H, s), 4.24(2H, brs), 6.60(1H, d, J=2.0Hz), 6.91(1H, ddd, J=1.6, 2.0, 8.8 Hz), 7.18(1H, d, J=5.6 Hz), 7.84(1H,d, J=8.8 Hz), 8.16(1H, dd, J=1.6, 5.6 Hz).

Preparation Example 34

N-t-Butoxycarbonyl-3-nitrophenethylamine

In tetrahydrofuran (130 ml) was dissolved 4.559 g of3-nitrophenethylamine (Preparation Example 27), and triethylamine (8.4ml) and di-t-butyl dicarbonate (6.6 g) were added thereto, followed bystirring at room temperature for 2 hours. The solvent was evaporated,and to the residue was added brine, followed by extracting with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated, to give the titlecompound (8.789 g, including impurities) as a yellow oil. The productwas subjected to the subsequent reaction as intact without furtherpurification.

¹H-NMR(CDCl₃) δ (ppm): 1.53(9H, s), 2.92(2H, t, J=7.6 Hz), 3.42(2H, dt,J=6.4, 6.8 Hz), 4.58(1H, brs), 7.48(1H, dd, J=7.2, 8.0 Hz), 7.54(1H, d,J=8.0 Hz), 8.07(1H, s), 8.10(1H, d, J=7.2 Hz).

Preparation Example 35

3-(2-t-Butoxycarbonlylaminoethyl)-aniline

Using N-t-butoxycarbonyl-3-nitrophenethylamine (8.789 g, includingimpurities, Preparation Example 34), the title compound (5.521 g, 76%)was obtained as a yellow oil in the same manner as in PreparationExample 29.

¹H-NMR(CDCl₃) δ (ppm): 1.44(9H, s), 2.70(2H, t, J=7.4 Hz), 3.36(2H,brq), 4.54(1H, brs), 6.54(1H, s), 6.57(1H, d, J=8.0 Hz), 6.60(1H, d,J=7.2 Hz), 8.10(1H, dd, J=7.2, 8.0 Hz).

Preparation Example 36

3-(2-t-Butoxycarbonylaminoethyl)-ethoxycarbonylaminobenzene

Using 3-(2-t-butoxycarbonylaminoethyl)-aniline (5.521 g, PreparationExample 35), the title compound (0.320 g) was obtained as a yellow oilin the same manner as in Preparation Example 29. The product wassubjected to the subsequent reaction as intact without furtherpurification.

¹H-NMR(CDCl₃) δ (ppm): 1.31(3H, t, J=7.2 Hz), 1.43(9H, s), 2.77(2H, t,J=7.4 Hz), 3.67(2H, brq), 4.22(2H, q, J=7.4 Hz), 4.55(1H, brs), 6.52(1H,brs), 6.89(1H, m), 7.24(1H, m).

Preparation Example 37

3-Ethoxycarbonylaminophenethylamine hydrochloride

In ethanol (15 ml) was dissolved 14.96 g of3-(2-t-butoxycarbonylaminoethyl)-ethoxycarbonylaminobenzene (PreparationExample 36). Under ice-cooling, hydrochloric acid (15 ml) was addedthereto, followed by stirring at room temperature for 20 minutes.Hydrochloric acid (12 ml) and ethanol (15 ml) were further addedthereto, followed by stirring at room temperature for 20 minutes. Then,hydrochloric acid (20 ml) and ethanol (30 ml) were further addedthereto, followed by stirring at room temperature for 30 minutes. Thesolvent was evaporated (azeotropic distillation with toluene), to givethe title compound (11.99 g) as pale yellow crystals.

¹H-NMR(DMSO-d₆) δ (ppm): 1.22(3H, t, J=7.2 Hz), 2.82(2H, m), 2.95(2H,m), 4.10(2H, q, J=7.2 Hz), 6.86(1H, d, J=7.6 Hz), 7.20(1H, dd, J=7.6,8.4 Hz), 7.31(1H, d, J=8.4 Hz), 7.36(1H, s), 8.05(2H, brs), 9.61(1H, s).

Preparation Example 38

6-Aminoethyl-1,2,3,4-tetrahydroisoquinoline

The title compound (4.226 g, including impurities) was obtained as ayellow oil according to the procedure described in Chem. Pharm. Bull.42(8), 1676 (1994), except using 3-ethoxycarbonylaminophenethylaminehydrochloride (4.7 g) obtained in Preparation Example 37.

¹H-NMR(CDCl₃) δ (ppm): 1.29(3H, t, J=7.2 Hz), 2.68(1H, brs), 2.83(3H,m), 3.73(2H, m), 4.20(2H, q, J=7.2 Hz), 6.77(1H, s), 6.94(1H, d, J=8.4Hz), 7.07(1H, d, J=8.4 Hz), 7.18(1H, brs).

Preparation Example 39

6-Ethoxycarbonylaminoisoquinoline

To 10 g of 6-aminoethyl-1,2,3,4-tetrahydroisoquinoline (PreparationExample 38) were added p-cymene (100 ml) and palladium-carbon (0.9 g),followed by heating under stirring at 195° C. in nitrogen atmosphere for1 hour. The catalyst was filtered off and washed ethanol, followed byevaporating the filtrate. The resulting crystals were washed withdiethyl ether and dried. The solvent was evaporated, to give the titlecompound (6.51 g, 66%) as pale yellow crystals.

¹H-NMR(CDCl₃) δ (ppm): 1.36(3H, t, J=7.2 Hz), 3.74(1H, m), 4.29(2H, q,J=7.2 Hz), 6.70(1H, d, J=2.0 Hz), 7.46(1H, dd, J=2.0, 8.8 Hz), 7.58(1H,d, J=6.0 Hz), 7.90(1H, d, J=8.8 Hz), 8.04(1H, brs), 8.46(1H, d, J=6.0Hz), 9.13(1H, s).

Preparation Example 40

6-Ethoxycarbonylaminoisoquinoline-N-oxide

The title compound (293 mg) was obtained as pale yellow crystals in thesame manner as in Preparation Example 22, except using6-ethoxycarbonylaminoisoquinoline (250 mg, Preparation Example 39).

¹H-NMR(DMSO-d₆) δ (ppm): 1.25(3H, t, J=7.2 Hz), 4.26(2H, q, J=7.2 Hz),7.61(1H, dd, J=2.0, 8.8 Hz), 7.79(1H, d, J=8.8 Hz), 7.81(1H, d, J=7.2Hz), 8.04(1H, dd, J=2.0, 7.2 Hz), 8.79(1H, s), 8.46(1H, d, J=6.0 Hz),9.13(1H, s).

Preparation Example 41

1-Chloro-6-ethoxycarbonylaminoisoquinoline

The title compound (173 mg, 60%, 2 steps) was obtained as pale yellowcrystals in the same manner as in Preparation Example 22, except using6-ethoxycarbonylaminoisoquinoline-N-oxide (250 mg).

¹H-NMR(CDCl₃) δ (ppm): 1.34(3H, t, J=7.2 Hz), 4.29(2H, q, J=7.2 Hz),7.36(1H, brs), 7.50(1H, d, J=5.6 Hz), 7.52(1H, dd, J=2.4, 9.2 Hz),8.11(1H, m), 8.19(1H, d, J=5.6 Hz), 8.22(1H, d, J=9.2 Hz).

Preparation Example 42

1-Methoxy-6-methoxycarbonylaminoisoquinoline

In dimethyl sulfoxide (45 ml) was dissolved 2.27 g of1-chloro-6-ethoxycarbonylaminoisoquinoline (Preparation Example 41). Tothe mixture was added 28% sodium methoxide solution (8.7 ml), followedby heating under stirring at 110° C. for 1.5 hours. After cooling toroom temperature as it was, an aqueous saturated ammonium chloride wasadded thereto and the mixture was extracted with ethyl acetate. Theextract was washed with brine, dried over anhydrous magnesium sulfateand the solvent was evaporated, to give the title compound (1.75 g, 84%)as a brown oil.

¹H-NMR(CDCl₃) δ (ppm): 3.74(3H, s), 4.03(3H, s), 7.05(1H, d, J=5.8 Hz),7.41(1H, dd, J=2.0, 9.2 Hz), 7.86(1H, d, J=5.8 Hz), 7.90(1H, brs),8.06(1H, d, J=9.22 Hz), 8.08(1H, brs).

Preparation Example 43

6-Amino-1-methoxyisoquinoline

The title compound (1.04 g, 99%) was obtained as light brown crystals inthe same manner as in Preparation Example 41, except using1-methoxy-6-methoxycarbonylaminoisoquinoline (1.75 g, PreparationExample 42) and methanol as a solvent.

¹H-NMR(CDCl₃) δ (ppm): 4.07(3H, s), 4.07(2H, brs), 6.78(1H, d, J=2.2Hz), 6.88(1H, dd, J=2.2, 8.8 Hz), 6.95(1H, d, J=6.0 Hz), 7.84(1H, d,J=6.0 Hz), 8.03(1H, d, J=8.8 Hz).

Preparation Example 44

N-Propynyl-(3-nitrophenethyl)amine

The title compound (3.070 g, 77%, including impurities) was obtained asa yellow oil in the same manner as in Preparation Example 28, exceptusing 3-nitrophenethylamine (3.0 g, Preparation Example 27) andpropionyl chloride (2.5 ml).

¹H-NMR(CDCl₃) δ (ppm): 1.14(3H, t, J=7.6 Hz), 2.19(2H, q, J=7.6 Hz),2.96(2H, t, J=6.8 Hz), 3.56(2H, dt, J=6.4, 6.8 Hz), 7.49(1H, dd, J=7.6,8.0 Hz), 7.55(1H, d, J=7.6 Hz), 8.07(1H, s), 8.10(1H, d, J=8.0 Hz).

Preparation Example 45

N-Propynyl-(3-aminophenethyl)amine

A similar reaction to that in Preparation Example 29 was performed usingN-propynyl-(3-nitrophenethyl)amine (3.070 g, Preparation Example 44).The resulting residue was purified by silica gel column, to give thetitle compound (0.857 g, 32%) as a pale yellow oil.

¹H-NMR(CDCl₃) δ (ppm): 1.12(3H, t, J=7.6 Hz), 2.19(2H, q, J=7.6 Hz),2.71(2H, t, J=6.8 Hz), 3.49(2H, dt, J=6.0, 6.8 Hz), 5.56(1H, brs),6.52(1H, s), 6.56(1H, d, J=7.6 Hz), 6.56(1H, d, J=7.6 Hz), 7.09(1H, dd,J=7.6, 7.6 Hz).

Preparation Example 46

N-Propynyl-(3-ethoxycarbonylaminophenethyl)amine

A similar reaction to that in Preparation Example 30 was performed usingN-propynyl-(3-aminophenethyl)amine (0.857 g, Preparation Example 45).The resulting residue was purified by silica gel column, to give thetitle compound (0.747 g, 61%) as a light-colored oil.

¹H-NMR(CDCl₃) δ (ppm): 1.12(3H, t, J=7.6 Hz), 1.30(3H, t, J=7.0 Hz),2.16(2H, q, J=7.6 Hz), 2.78(2H, t, J=6.8 Hz), 3.50(2H, dt, J=6.0, 6.8Hz), 4.21(2H, q, J=7.0 Hz), 6.67(1H, brs), 6.87(1H, d, J=6.8 Hz),7.00(1H, brs), 7.22(1H, dd, J=6.8, 8.4 Hz), 7.26(1H, d, J=8.4 Hz),7.28(1H, s).

Preparation Example 47

6-Ethoxycarbonylamino-1-ethylisoquinoline

The procedures of Preparation Examples 31 and 32 were repeated, exceptusing N-propynyl-(3-ethoxycarbonylaminophenethyl)amine (0.747 g,Preparation Example 46), to give6-ethoxycarbonylamino-1-ethyl-3,4-dihydroxyisoquinoline as browncrystals, and then the title compound (0.516 g, 75%, 2 steps) as ayellow oil.

The data of the intermediate and the title compound are as follows.

6-Ethoxycarbonylamino-1-ethyl-3,4-dihydroisoquinoline

¹H-NMR(CDCl₃) δ (ppm): 1.21(3H, t, J=7.6 Hz), 1.30(3H, t, J=7.0 Hz),2.66(2H, t, J=7.4 Hz), 2.74(2H, q, J=7.6 Hz), 3.64(2H, t, J=7.4 Hz),4.23(2H, q, J=7.0 Hz), 7.32(1H, d, J=8.4 Hz), 7.37(1H, s), 7.43(1H, d,J=8.4 Hz), 7.79(1H, s).

6-Ethoxycarbonylamino-1-ethylisoquinoline

¹H-NMR(CDCl₃) δ (ppm): 1.32(3H, t, J=7.0 Hz), 1.41(3H, t, J=7.6 Hz),3.27(2H, q, J=7.6 Hz), 4.27(2H, q, J=7.0 Hz), 7.40(1H, d, J=6.0 Hz),7.52(1H, dd, J=2.0, 8.8 Hz), 7.89(1H, s), 8.02(1H, d, J=2.0 Hz),8.25(1H, d, J=8.8 Hz), 8.34(1H, J=6.0 Hz).

Preparation Example 48

6-Amino-1-ethylisoquinoline

The title compound (0.320 g, 88%) was obtained as pale yellow crystalsin the same manner as in Preparation Example 33, except using6-ethoxycarbonylamino-1-ethylisoquinoline (0.516 g, Preparation Example47).

¹H-NMR(CDCl₃) δ (ppm): 1.31(3H, t, J=7.2 Hz), 3.21(2H, q, J=7.2 Hz),4.20(2H, brs), 6.82(1H, d, J=2.4 Hz), 6.95(1H, dd, J=2.4, 8.8 Hz),7.21(1H, d, J=6.0 Hz), 7.94(1H, d, J=8.8 Hz), 8.24(1H, d, J=6.0 Hz).

Preparation Example 49

1-Ethoxy-4-(3-nitrophenyl)propan-1-ene

Methoxymethylphosphonium chloride (31.1 g) was suspended intetrahydrofuran (200 ml), followed by adding potassium t-butoxide (10.2g) thereto under ice-cooling. At the time when the reaction mixturebecame red, a solution of 3-nitroacetophenone (10 g) in tetrahydrofuran(100 ml) was added thereto by portions using a pipette. After stirringat room temperature for 2.5 hours, an aqueous saturated ammoniumchloride was added thereto under ice-cooling. The mixture was extractedwith ethyl acetate, and the extract was washed with brine, dried overanhydrous magnesium sulfate and the solvent was evaporated. Theresulting residue was purified by silica gel column, to give the titlecompound (8.010 g) as a yellow oil.

Preparation Example 50

2-(3-Nitrophenyl)propanal

To 1-methoxy-4-(3-nitrophenyl)propan-1-ene (8.010 g) was added 2 Nhydrochloric acid (150 ml), followed by heating under stirring at 80° C.for 4 hours. Then, hydrochloric acid (5 ml) was added thereto, followedby heating under reflux for 2.5 hours. After cooling, the reactionmixture was neutralized with an aqueous sodium hydroxide and extractedwith ethyl acetate. The extract was washed with brine, dried overanhydrous magnesium sulfate and the solvent was evaporated, to give thetitle compound (7.531 g) as a yellow oil.

Preparation Example 51

2-(3-Nitrophenyl)propan-1-ol

In ethanol (100 ml) was dissolved 7.531 g of 2-(3-nitrophenyl)propanal.Under ice-cooling, sodium borohydride (1.9 g) was added thereto,followed by stirring at room temperature for 1 hour. To the mixture wasadded brine, followed by extracting with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated. The resulting residue was purified by silica gelcolumn, to give the title compound (6.275 g, 57.19% in 3 steps) as abrown oil.

¹H-NMR(CDCl₃) δ (ppm): 1.34(3H, d, J=6.8 Hz), 1.51(1H, brs), 3.09(1H,tq, J=6.8, 6.8 Hz), 3.78(2H, d, J=6.8 Hz), 7.50(1H, dd, J=7.6, 8.4 Hz),7.60(1H, ddd, J=1.2, 1.6, 7.6 Hz), 8.10(1H, ddd, J=1.2, 2.4, 8.4 Hz),8.13(1H, dd, J=1.6, 2.4 Hz).

Preparation Example 52

2-(3-Nitrophenyl)propylamine

The title compound was obtained as a yellow oil by the procedures ofPreparation Examples 26 and 27, except using2-(3-nitrophenyl)propan-1-ol (1.908 g, Preparation Example 51).

Preparation Example 53

1-t-Butoxycarbonylamino-2-(3-nitrophenyl)propane

A similar reaction to that in Preparation Example 35 was performed using2-(3-nitrophenyl)propylamine obtained in Preparation Example 52. Theresulting residue was purified by silica gel column, to give the titlecompound (2.626 g) as a yellow oil.

¹H-NMR(CDCl₃) δ (ppm): 1.31(3H, d, J=6.8 Hz), 1.40(9H, s), 3.10(1H, m),3.26(1H, m), 3.38(1H, m), 7.49(1H, dd, J=7.6, 8.4 Hz), 7.56(1H, d, J=7.6Hz), 8.08(1H, s), 8.10(1H, d, J=8.4 Hz).

Preparation Example 54

2-(3-Aminophenyl)-1-t-butoxycarbonylaminopropane

The title compound was obtained as a yellow oil by the procedure ofPreparation Example 29, except using the above prepared1-t-butoxycarbonylamino-2-(3-nitrophenyl)propane (2.626 g).

Preparation Example 55

1-t-Butoxycarbonylamino-2-(3-ethoxycarbonylaminophenyl)propane

A similar reaction to that in Preparation Example 30 was performed usingthe above-prepared 2-(3-aminophenyl)-1-t-butoxycarbonylaminopropane. Theresulting residue was purified by silica gel column, to give the titlecompound (2.960 g, 77.56% in 3 steps) as a brown oil.

¹H-NMR(CDCl₃) δ (ppm): 1.25(3H, d, J=7.6 Hz), 1.31(3H, t, J=7.2 Hz),1.41(9H, s), 2.90(1H, m), 3.18(1H, ddd, J=4.2, 7.6, 9.2 Hz), 3.39(1H,m), 4.42(2H, q, J=7.6 Hz), 4.45(1H, brs), 6 87(1H, brs), 6.94(1H, m),7.22(3H, m).

Preparation Example 56

6-Ethoxycarbonylamino-4-methyl-1,2,3,4-tetrahydroisoquinoline

The title compound (2.967 g, crude) was obtained as a yellow solid bythe procedures of Preparation Examples 38 and 39, except using1-t-butoxycarbonylamino-2-(3-ethoxycarbonylaminophenyl)propane (2.960 g,Preparation Example 55)

Preparation Example 57

6-Ethoxycarbonylamino-4-methylisoquinoline

The title compound (2.061 g, crude) was obtained as pale yellow crystalsby a similar reaction to that in Preparation Example 40, except usingthe above-prepared6-ethoxycarbonylamino-4-methyl-1,2,3,4-tetrahydroisoquinoline (2.967 g,crude).

¹H-NMR(CDCl₃) δ (ppm): 1.36(3H, t, J=7.2 Hz), 2.59(3H, s), 4.30(2H, q,J=7.2 Hz), 7.12(1H, d, J=2.0 Hz), 7.49(1H, dd, J=2.0, 8.8 Hz), 7.91(1H,d, J=8.8 Hz), 8.12(1H, s), 8.32(1H, s), 9.00(1H, s).

Preparation Example 58

6-Amino-4-methylisoquinoline

The above-prepared 6-ethoxycarbonylamino-4-methylisoquinoline (2.061 g,crude) was subjected to a reaction in the same manner as in PreparationExample 30. The resulting crystals were washed with diethyl ether anddried, to give the title compound (0.403 g, 27.75% in 4 steps) as paleyellow crystals.

¹H-NMR(CDCl₃) δ (ppm): 2.48(3H, s), 4.18(2H, brs), 6.95(1H, d, J=2.0Hz), 7.00(1H, dd, J=2.0, 8.8 Hz), 7.76(1H, d, J=8.8 Hz), 8.19(1H, s),8.86(1H, s).

Preparation Example 59

2-(3-Nitrophenyl)butan-1-ol

The title compound (5.456 g, 50.08% in 3 steps) was obtained as a yellowoil by the procedures of Preparation Examples 52 to 55, except using3-nitropropiophenone (10 g).

¹H-NMR(CDCl₃) δ (ppm): 0.86(3H, t, J=7.4 Hz), 1.63(1H, m), 1.85(1H, m),3.24(1H, m), 3.83(2H, m), 7.50(1H, dd, J=7.2, 8.0 Hz), 7.57(1H, d, J=8.0Hz), 8.10(1H, s), 8.13(1H, d, J=7.2 Hz).

Preparation Example 60

2-(3-Nitrophenyl)butylamine

The title compound (5.247 g) was obtained as a yellow oil by theprocedures of Preparation Examples 26 and 27, except using2-(3-nitrophenyl)butan-1-ol (5.456 g, Preparation Example 59).

Preparation Examples 61

1-t-Butoxycarbonylamino-2-(3-nitrophenyl)butane

Then, the above-prepared 2-(3-nitrophenyl)butylamine (5.247 g) wassubjected to the reaction in the same manner as in Preparation Example27. The resulting residue was purified by silica gel column, to give thetitle compound (7.679 g) as a pale yellow oil.

¹H-NMR(CDCl₃) δ (ppm): 0.83(3H, t, J=7.4 Hz), 1.39(9H, s), 1.63(1H, m),1.79(1H, m), 2.84(1H, m), 3.21(1H, m), 3.52(1H, m), 4.42(1H, brs),7.49(1H, d, J=7.6 Hz), 7.52(1H, dd, J=6.8, 7.6 Hz), 8.04(1H, s),8.10(1H, d, J=6.8 Hz).

Preparation Example 62

2-(3-Aminophenyl)-1-t-butoxycarbonylaminobutane

The title compound (6.311 g, 85.40% in 4 steps) was obtained as a yellowoil by the procedure of Preparation Example 29, except using1-t-butoxycarbonylamino-2-(3-nitrophenyl)butane (7.679 g).

Preparation Example 63

1-t-Butoxycarbonylamino-2-(3-ethoxycarbonylaminophenyl)butane

The above-prepared compound was then treated in the same manner as inPreparation Example 30, to give the title compound (8.230 g, crude) asan orange solid.

¹H-NMR(CDCl₃) δ (ppm): 0.81(3H, t, J=7.4 Hz), 1.31(3H, t, J=7.2 Hz),1.40(9H, s), 1.55(1H, m), 1.68(1H, m), 2.63(1H, m), 3.14(1H, ddd, J=4.8,8.8, 13.6 Hz), 3.52(1H, m), 4.22(2H, q, J=7.2 Hz), 4.38(1H, brs), 663(1H, brs), 6.87(1H, m), 7.23(3H, m).

Preparation Example 64

6-Ethoxycarbonylamino-4-ethyl-1,2,3,4-tetrahydroisoquinoline

The title compound was obtained as a brown oil by the procedures ofPreparation Examples 38 and 39, except using1-t-butoxycarbonylamino-2-(3-ethoxycarbonylaminophenyl)butane (8.230 g,crude, Preparation Example 63).

Preparation Example 65

6-Ethoxycarbonylamino-4-ethyl-isoquinoline

The above-prepared6-ethoxycarbonylamino-4-ethyl-1,2,3,4-tetrahydroisoquinoline (3.0 g) wassubjected to the reaction in the same manner as in Preparation Example40. The resulting crude crystals were washed with ethanol-diethyl etherand dried, to give the title compound as orange crystals.

¹H-NMR(DMSO-d₆) δ (ppm): 1.27(3H, t, J=7.2 Hz), 1.28(3H, t, J=7.2 Hz),2.91(2H, q, J=7.2 Hz), 4.18(2H, q, J=7.2 Hz), 7.64(1H, d, J=8.8 Hz),8.00(1H, d, J=8.8 Hz), 8.25(1H, s), 8.27(1H, s), 8.98(1H, s), 10.12(1H,s).

Preparation Example 66

6-Amino-4-ethyl-isoquinoline

The above-prepared 6-ethoxycarbonylamino-4-ethylisoquinoline wassubjected to the reaction in the same manner as in Preparation Example30. The resulting residue was purified by NH-silica gel column, and theresulting crude crystals were washed with diethyl ether and dried, togive the title compound (0.637 g) as orange crystals.

¹H-NMR(CDCl₃) δ (ppm): 1.35(3H, t, J=7.6 Hz), 2.92(2H, q, J=7.6 Hz),4.17(2H, brs), 6.99(1H, d, J=8.4 Hz), 7.00(1H, s), 7.77(1H, d, J=8.4Hz), 8.21(1H, s), 8.86(1H, s).

Preparation Example 67

Diethyl Methyl-(3-nitrobenzyl)malonate

In ethanol (45 ml) was dissolved sodium (0.7 g), and diethylmethylmalonate (5.26 ml) and 3-nitrobenzyl chloride (5 g) were addedthereto, followed by heating under reflux for 2 hours. The reactionmixture was ice-cooled, an aqueous saturated ammonium chloride was addedthereto, followed by extracting with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated, to give the title compound (9.724 g) as a paleyellow oil.

¹H-NMR(CDCl₃) δ (ppm): 1.27(6H, t, J=7.2 Hz), 1.37(3H, s), 3.32(2H, s),4.21(4H, q, J=7.2 Hz), 7.44(1H, d, J=7.6 Hz), 7.48(1H, dd, J=7.6, 7.6Hz), 8.03(1H, s), 8.11(1H, d, J=7.6 Hz).

Preparation Example 68

Ethyl 1-Methyl -2-(3-nitrophenyl)propionate

In dimethyl sulfoxide (30 ml) was dissolved the above-prepared diethylmethyl(3-nitrobenzyl)malonate (9.724 g), and water (0.54 ml) and lithiumchloride (2.54 g) were added thereto, followed by heating under refluxat 190° C. for 3.5 hours. After cooling as it was, water was addedthereto, followed by extracting with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated, to give the title compound (5.071 g, 73.35% in 2steps) as a brown oil.

¹H-NMR(CDCl₃) δ (ppm): 1.20(3H, t, J=7.2 Hz), 1.21(3H, d, J=7.2 Hz),2.79(2H, m), 3.10(1H, m), 4.10(2H, q, J=7.2 Hz), 7.45(1H, dd, J=7.6, 8.0Hz), 7.52(1H, d, J=7.6 Hz), 8.06(1H, s), 8.08(1H, d, J=8.0 Hz).

Preparation Example 69

1-Methyl -2-(3-nitrophenyl)propionic acid

In ethanol (50 ml) was dissolved 5.071 g of ethyl1-methyl-2-(3-nitrophenyl)propionate (Preparation Example 68), and 5 Nsodium hydroxide aqueous solution (43 ml) was added thereto, followed byheating under reflux for 2.5 hours. After cooling as it was, diethylether and water were added thereto, to separate the aqueous layer. Theorganic layer was extracted with brine. The aqueous layers werecombined, acidified with dilute hydrochloric acid, and then extractedwith diethyl ether. The extract was washed with brine, dried overanhydrous magnesium sulfate and the solvent was evaporated. Theresulting residue was purified by silica gel column, to give the titlecompound (2.918 g, 65.27%) as a red oil.

¹H-NMR(CDCl₃) δ (ppm): 1.24(3H, d, J=6.0 Hz), 2.83(2H, s), 3.16(1H, m),7.47(1H, dd, J=7.2, 8.0 Hz), 7.54(1H, d, J=7.2 Hz), 8.08(1H, s),8.10(1H, d, J=8.0 Hz).

Preparation Example 69

N-Boc-1-methyl-2-(3-nitrophenyl)ethylamine

In t-butanol (36 ml) was dissolved 2.918 g of1-methyl-2-(3-nitrophenyl)propionic acid (Preparation Example 69), andtriethylamine (4.09 ml) and diphenylphosphorylazide were added thereto,followed by heating under reflux for 2.5 hours. After standing to cool,the solvent was evaporated. To the residue was added saturated sodiumbicarbonate, followed by extracting with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated. The resulting residue was purified by silica gelcolumn, to give the title compound (2.117 g, 54.14%) as yellow crystals.

¹H-NMR(CDCl₃) δ (ppm): 1.13(3H, d, J=6.8 Hz), 2.82(1H, m), 2.92(1H, m),3.94(1H, brs), 7.47(1H, dd, J=7.2, 8.0 Hz), 7.54(1H, d, J=7.2 Hz),8.05(1H, s), 8.09(1H, d, J=8.0 Hz).

Preparation Example 71

N-Boc-2-(3-aminophenyl)-1-methylethylamine

N-Boc-1-methyl-2-(3-aminophenyl)-1-methylethylamine (2.117 g,Preparation Example 70) was subjected to the reaction in the same manneras in Preparation Example 29. After extracting, the resulting residuewas purified by silica gel column, to give the title compound (0.976 g,51.63%) as a yellow oil.

Preparation Example 72

N-Boc-1-methyl -2-(3-ethoxycarbonylaminophenyl)ethylamine

The title compound (1.173 g, crude) was obtained as a yellow oil by theprocedure of Preparation Example 30, except usingN-Boc-2-(3-aminophenyl)-1-methylethylamine (0.976 g). The obtainedcompound was subjected to a subsequent reaction as intact withoutfurther purification.

¹H-NMR(CDCl₃) δ (ppm): 1.09(3H, d, J=6.4 Hz), 1.31(3H, t, J=7.2 Hz),1.43(9H, s), 2.62(1H, dd, J=6.8 Hz, 13.2 Hz), 2.82(1H, m), 3.88(1H, m),4.22(2H, q, J=7.2 Hz), 4.38(1H, m), 6.56(1H, m), 6.89(1H, d, J=6.8 Hz),7.18(1H, s), 7.22(1H, dd, J=6.8, 8.0 Hz), 7.23(1H, d, J=8.0 Hz).

Preparation Example 73

2-(3-Ethoxycarbonylaminophenyl)-1-methylethylamine hydrochloride

In ethanol (5 ml) was dissolved 1.173 g ofN-Boc-1-methyl-2-(3-ethoxycarbonylaminophenyl)ethylamine (crude), andhydrochloric acid (5 ml) was added thereto, followed by stirring at roomtemperature for 1.5 hours. Then, hydrochloric acid (2.5 ml) was furtheradded thereto, followed by stirring at room temperature for 2 hours. Thesolvent was evaporated, to give the title compound (1.148 g, crude) as ayellow oil. The obtained compound was subjected to the subsequentreaction as intact without further purification.

¹H-NMR(DMSO-d₆) δ (ppm): 1.03(3H, d, J=6.8 Hz), 1.22(3H, t, J=7.2 Hz),2.55(1H, m), 2.95(1H, m), 3.32(1H, m), 4.10(2H, q, J=7.2 Hz), 6.84(1H,d, J=7.2 Hz), 7.21(1H, dd, J=7.2, 7.2 Hz), 7.29(1H, d, J=7.2 Hz),7.35(1H, s), 8.00(1H, brs), 9.60(1H, s).

Preparation Example 74

6-Ethoxycarbonylamino-3-methyl-1,2,3,4-tetrahydroisoquinoline

The title compound (0.441 g) was obtained by performing the reaction bythe procedure described in Chem. Pharm. Bull. 42(8), 1676 (1994) using2-(3-ethoxycarbonylaminophenyl)-1-methylethylamine hydrochloride (1.148g, Preparation Example 73) and purifying the product by NH-silica gelcolumn.

¹H-NMR(CDCl₃) δ (ppm): 1.24(3H, d, J=6.4 Hz), 1.30(3H, t, J=7.2 Hz),2.48(1H, dd, J=10.0 Hz, 16.4 Hz), 2.75(1H, dd, J=3.6 Hz, 16.4 Hz),3.01(1H, m), 4.03(2H, brq), 4.21(2H, q, J=7.2 Hz), 6.66(1H, s), 6.95(1H,d, J=8.4 Hz), 7.09(1H, d, J=8.4 Hz), 7.14(1H, s).

Preparation Example 75

6-Ethoxycarbonylamino-3-methylisoquinoline

The title compound (0.356 g) was obtained by the procedure ofPreparation Example 39, except using the above-prepared6-ethoxycarbonylamino-3-methyl-1,2,3,4-tetrahydroisoquinoline (0.441 g).

¹H-NMR(CDCl₃) δ (ppm): 1.34(3H, t, J=7.2 Hz), 2.67(3H, s), 4.28(2H, q,J=7.2 Hz), 7.08(1H, brs), 7.39(1H, dd, J=2.0, 8.8 Hz), 7.40(1H, s),7.85(1H, d, J=8.8 Hz), 7.94(1H, brs), 9.05(1H, s).

Preparation Example 76

6-Amino-3-methylisoquinoline

The above-prepared 6-ethoxycarbonylamino-3-methylisoquinoline (0.356 g)was subjected to the reaction in the same manner as in PreparationExample 33, to give crude crystals (0.182 g). The crystals were washedwith diethyl ether and dried, to give the title compound (93 mg) as paleyellow crystals.

¹H-NMR(CDCl₃) δ (ppm): 2.63(3H, s), 4.14(2H, brs), 6.77(1H, d, J=2.0Hz), 6.93(1H, dd, J=2.0, 8.8 Hz), 7.18(1H, s), 7.72(1H, d, J=8.8 Hz),8.9

Example 1

N-(8-Bromoquinolin-3-yl)-3-pyridinesulfonamide

In pyridine (5 ml) was dissolved 3-amino-8-bromoquinoline (PreparationExample 5) was dissolved in pyridine (5 ml), and 3-pyridinesulfonylchloride (254 mg) was added thereto, followed by stirring at roomtemperature for 30 minutes. After the completion of the reaction, thereaction mixture was poured onto brine, and extracted with ethylacetate. The organic layer was dried over magnesium sulfate and thenconcentrated. The resulting crude crystals were washed with ethylacetate and IPA, to give the title compound (270 mg).

¹H-NMR(DMSO-d₆) δ (ppm): 7.47(1H, t, J=8.0 Hz), 7.52-7.60(1H, m),7.99-8.03(2H, m), 8.10(1H, d, J=2.4 Hz), 8.18-8.22(1H, m), 8.71(1H, d,J=2.4 Hz), 8.78(1H, dd, J=1.6 Hz, 4.8 Hz), 8.98(1H, d, J=2.4 Hz),11.23(1H, br s).

Example 2

N-(5-Bromoquinolin-2-yl)-5-methyl-3-pyridinesulfonamide

The title compound was obtained from 2-amino-5-bromoquinoline(Preparation Example 1) and 5-methyl-3-pyridinesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 2.37(3H, s), 7.58-7.72(4H, m), 8.11(1H, br s),8.37(1H, d, J=9.6 Hz), 8.59(1H, d, J=1.2 Hz), 8.86(1H, br s).

Example 3

6-Amino-N-(8-bromoquinolin-3-yl)-3-pyridinesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Preparation Example 5) and 6-amino-3-pyridinesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 6.40(1H, d, J=8.8 Hz), 6.93(2H, brs), 7.44(1H,t, J=8.0 Hz), 7.65(1H, dd, J=2.4 Hz, 8.8 Hz), 7.96-7.99(2H, m), 8.01(1H,d, J=2.4 Hz), 8.31(1H, d, J=2.4 Hz), 8.70(1H, d, J=2.4 Hz), 10.73(1H, brs).

Example 4

N-(8-Bromoquinolin-3-yl)-4-cyanobenzenesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Preparation Example 5) and 4-cyanobenzenesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 7.46(1H, t, J=8.0 Hz), 7.96-8.07(7H, m),8.70(1H, d, J=2.4 Hz), 11.27(1H, br s).

Example 5

6-Chloro-N-(8-bromoquinolin3-yl)-3-pyridinesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Preparation Example 5) and 6-chloro-3-pyridinesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 7.47(1H, t, J=8.0 Hz), 7.71(1H, d, J=8.4 Hz),7.99-8.03(2H, m), 8.10(1H, d, J=2.4 Hz), 8.20(1H, dd, J=8.4 Hz),8.71(1H, d, J=2.4 Hz), 8.83(1H, d, J=2.4 Hz), 10.73(1H, br s).

Example 6

N-(8-Bromoquinolin-3-yl)-4-(N-ethylsulfamoyl)benzenesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Preparation Example 5) and 4-(N-ethylsulfamoyl)benzenesulfonyl chlorideby the procedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 0.82(3H, t, J=7.2 Hz), 2.69-2.76(2H, m),7.45(1H, t, J=8.4 Hz), 7.75(1H, t, J=5.6 Hz), 7.90-8.04(7H, m), 8.70(1H,d, J=2.8 Hz), 11.18(1H, br s).

Example 7

N-(8-Bromoquinolin-3-yl)-5-cyano-2-pyridinesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Preparation Example 5) and 5-cyano-3-pyridinesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 7.46(1H, t, J=8.0 Hz), 7.95(1H, d, J=8.0 Hz),8.01(1H, d, J=8.0 Hz), 8.11(1H, d, J=2.4 Hz), 8.21(1H, d, J=8.4 Hz),8.57(1H, dd, J=2.0 Hz, 8.4 Hz), 8.79(1H, d, J=2.4 Hz), 9.14(1H, d, J=2.0Hz), 11.49(1H, br s).

Example 8

N-(8-Cyanoquinolin-3-yl) 3-pyridinesulfonamide

The title compound was obtained from 3-amino-8-cyanoquinoline(Preparation Example 7) and 3-pyridinesulfonyl chloride by the procedureof Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 7.59(1H, dd, J=4.8 Hz, 8.0 Hz), 7.70(1H, t,J=8.0 Hz), 8.21-8.25(3H, m), 8.33(1H, d, J=8.0 Hz), 8.77-8.79(2H, m),9.01(1H, d, J=2.8 Hz), 11.34(1H, br s).

Example 9

N-(8-Cyanoquinolin-3-yl)-4-cyanobenzenesulfonamide

The title compound was obtained from 3-amino-8-cyanoquinoline(Preparation Example 7) and 4-cyanobenzenesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 7.71(1H, t, J=8.0 Hz), 7.96-8.07(4H, m),8.18(1H, d, J=2.8 Hz), 8.24(1H, d, J=8.0 Hz), 8.31(1H, d, J=8.0 Hz),8.78(1H, d, J=2.8 Hz), 11.37(1H, br s).

Example 10

N-(5-Bromoquinolin-2-yl)-3-pyridinesulfonamide

The title compound was obtained from 2-amino-5-bromoquinoline(Preparation Example 1) and 3-pyridinesulfonyl chloride by the procedureof Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 7.57-7.61(3H, m), 7.70-7.72(2H, m), 8.28(1H,br), 8.38(1H, d, J=9.6 Hz), 8.75(1H, dd, J=1.2 Hz, 4.8 Hz), 9.07(1H,br).

Example 11

N-(8-Bromoquinolin-3-yl)-5-indanesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Preparation Example 5) and 5-indanesulfonyl chloride by the procedureof Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 1.92-2.01(2H, m), 2.81-2.86(4H, m), 7.34(1H, d,J=8.0 Hz), 7.44(1H, t, J=8.0 Hz), 7.60(1H, dd, J=1.6 Hz, 8.0 Hz),7.70(1H, d, J=1.6 Hz), 7.95(1H, d, J=8.0 Hz), 7.97(1H, d, J=8.0 Hz),8.03(1H, d, J=2.4 Hz), 8.71(1H, d, J=2.4 Hz), 10.93(1H, br s).

Example 12

N-(8-Iodoquinolin-3-yl)-N*-acetyl-5-indolinesulfonamide

The title compound was obtained from 3-amino-8-iodoquinoline(Preparation Example 6) and N-acetyl-6-indolinesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 2.11(3H, s), 3.11(2H, t, J=8.4 Hz), 4.06(2H, t,J=8.4 Hz), 7.28(1H, t, J=8.0 Hz), 7.65-7.68(2H, m), 7.93-7.96(2H, m),8.05(1H, d, J=9.2 Hz), 8.22(1H, dd, J=1.2 Hz, 7.6 Hz), 8.64(1H, d, J=2.4Hz), 10.87(1H, br s).

Example 13

N-(8-Bromoquinolin-3-yl)-3-quinolinesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Preparation Example 5) and 3-quinolinesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 7.38(1H, t, J=8.0 Hz), 7.70-7.74(1H, m),7.90-8.00(3H, m), 8.07(1H, d, J=8.0 Hz), 8.13(1H, d, J=2.4 Hz), 8.19(1H,dd, J=0.8 Hz, 8.4 Hz), 8.75(1H, d, J=2.4 Hz), 9.00-9.01(1H, m), 9.19(1H,d, J=2.4 Hz), 11.31(1H, br s).

Example 14

N-(8-Bromoquinolin-3-yl)-N*-acetyl-1,2,3,4-tetrahydroquinoline-6-sulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Preparation Example 5) andN-acetyl-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride by theprocedure of Example 1.

¹H-NMR(CDCl₃) δ (ppm): 1.69(3H, s), 1.86-2.01(2H, m), 2.77(2H, t,J=6.4Hz), 3.65-3.76(2H, m), 7.11-7.18 (1H, m), 7.38(1H, t, J=7.6Hz),7.42-7.49(1H, m), 7.77 (1H, dd, J=1.2 Hz, J=7.6 Hz), 7.93 (1H, dd, J=1.2Hz, J=7.6 Hz), 8.22 (1H, d, J=2.4 Hz), 8.72(1H, J=2.4 Hz).

Example 15

N-(8-Iodoquinolin-3-yl)-4-isoquinolinesulfonamide

The title compound was obtained from 3-amino-8-iodoquinoline(Preparation Example 6) and 4-isoquinolinesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 7.26(1H, t, J=8.0 Hz), 7.82-7.86(1H, m),7.93-7.95(1H, m), 7.98(1H, d, J=2.4 Hz), 8.02-8.06(1H, m), 8.19(1H, dd,J=1.2 Hz, 7.6 Hz), 8.27(1H, d, J=8.4 Hz), 8.59(1H, d, J=2.4 Hz),8.67(1H, d, J=8.4 Hz), 9.12(1H, s), 9.52(1H, s), 11.57(1H, br s).

Example 16

4-Cyano-N-(8-iodoquinolin-3-yl)-benzenesulfonamide

The title compound was obtained from 3-amino-8-iodoquinoline(Preparation Example 6) and 4-cyanobenzenesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 7.31(1H, t, J=8.0 Hz), 7.96-8.04(6H, m),8.26(1H, dd, J=1.2 Hz, 7.2 Hz), 8.65(1H, d, J=2.8 Hz), 11.24(1H, br s).

Example 17

N-(8-Iodoquinolin-3-yl)-3-pyridinesulfonamide

The title compound was obtained from 3-amino-8-iodoquinoline(Preparation Example 6) and 3-pyridinesulfonyl chloride by the procedureof Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 7.31(1H, t, J=8.0 Hz), 7.57-7.60(1H, m),7.99(1H, d, J=1.2 Hz, 8.4 Hz), 8.04(1H, d, J=2.8 Hz), 8.18-8.21(1H, m),8.26(1H, dd, 1.2 Hz, 7.2 Hz), 8.66(1H, d, J=2.8 Hz), 8.77(1H, dd, J=1.6Hz, 4.8 Hz), 8.98(1H, d, J=2.8 Hz), 11.20(1H, br s).

Example 18

N-(5-Bromoquinolin-2-yl)-4-cyanobenzenesulfonamide

The title compound was obtained from 2-amino-5-bromoquinoline(Preparation Example 1) and 4-cyanobenzenesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(DMSO-d₆) δ (ppm): 7.57-7.73(4H, m), 8.00-8.08(4H, m), 8.38(1H, d,J=8.8 Hz).

Example 19

N-(8-Bromoquinolin-3-yl)-6-ethyl-3-pyridinesulfonamide

Pyridine (0.5 ml) and a solution of 6-ethyl-3-pyridinesulfonyl chloride(30 mg) in methylene chloride (0.5 ml) were added to3-amino-8-bromoquinoline (18 mg, Preparation Example 5) at 0° C. Afterstirring at room temperature for 30 minutes, water was added thereto andthe mixture was extracted with ethyl acetate. The extract was purifiedby preparative TLC (hexane-ethyl acetate=1:1), to give the titlecompound (20 mg).

¹H-NMR(CDCl₃) δ (ppm): 1.25(3H, t, J=7.5 Hz), 2.70(2H, q, J=7.50 Hz),7.34-7.98(5H, m), 8.19(1H, d, J=3.3 Hz), 8.54(1H, s), 8.83(1H, d, J=3.3Hz).

Example 20

4-Chloro-N-(5-chloroquinolin-2-yl)-benzenesulfonamide

Pyridine (1 ml) and 4-chlorobenzenesulfonyl chloride (255 mg) were addedto 2-amino-5-chloroquinoline (119 mg, Preparation Example 2) at roomtemperature. After stirring at room temperature for 3 days, water wasadded thereto and the mixture was extracted with ethyl acetate. Theethyl acetate layer was dried over sodium sulfate and concentrated.Then, the resulting solid was washed with methanol, to give the titlecompound (20 mg).

¹H-NMR(CDCl₃) δ (ppm): 6.96(1H, d, J=9.7 Hz), 7.34(1H, d, J=8.4 Hz),7.42-7.48(3H, m), 7.54(1H, t, J=8.4 Hz), 7.94(2H, d, J=6.3 Hz), 8.29(1H,d, J=9.7 Hz).

Example 21

N-(8-Chloroquinolin-3-yl)-6-ethyl -3-pyridinesulfonamide

The title compound was obtained from 3-amino-8-chloroquinoline(Preparation Example 9) and 6-ethyl-3-pyridinesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(CDCl₃) δ (ppm): 1.28(3H, t, J=8.3 Hz), 2.86(2H, q, J=8.3 Hz),7.24(1H, d, J=8.0 Hz), 7.49(1H, t, J=8.0 Hz), 7.73(1H, d, J=8.0 Hz),7.78(1H, d, J=8.0 Hz), 7.95(1H, dd, J=8.0 Hz 2.1 Hz), 8.18(1H, d, J=2.5Hz), 8.67(1H, d, J=2.5 Hz), 8.93(1H, d, J=2.1 Hz).

Example 22

N-(5-Chloroquinolin-2-yl -6-ethyl-3-pyridinesulfonamide

The title compound was obtained from 2-amino-5-chloroquinoline(Preparation Example 2) and 6-ethyl-3-pyridinesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(CDCl₃) δ (ppm): 1.32(3H, t, J=8.3 Hz), 2.89(2H, q, J=8.3 Hz),6.97(1H, d, J=9.4 Hz), 7.29(1H, d, J=8.0 Hz), 7.35(1H, d, J=8.0 Hz),7.44(1H, d, J=8.0 Hz), 7.56(1H, t, J=8.0 Hz), 8.18(1H, dd, J=8.0 Hz, 2.6Hz), 8.30(1H, d, J=9.4 Hz), 9.10(1H, d, J=2.6 Hz).

Example 23

N-(8-Chloroquinolin-3-yl)-benzenesulfonamide

The title compound was obtained from 3-amino-8-chloroquinoline(Preparation Example 9) and benzenesulfonyl chloride by the procedure ofExample 1.

¹H-NMR(CDCl₃) δ (ppm): 7.30-7.48(6H, m), 7.84(2H, d, J=7.4 Hz), 8.11(1H,d, J=3.1 Hz), 8.66(1H, d , J=3.1 Hz).

Example 24

4-Cyano-N-(5-chloroquinolin-2-yl)-benzenesulfonamide

The title compound was obtained from 2-amino-5-chloroquinoline(Preparation Example 2) and 4-cyanobenzenesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(CDCl₃) δ (ppm): 6.96(1H, d, J=9.5 Hz), 7.35(1H, d, J=8.7 Hz),7.45(1H, d, J=8.7 Hz), 7.57(1H, t, J=8.7 Hz), 7.78(2H, d, J=8.9 Hz),8.10(2H, d, J=8.9 Hz), 8.33(1H, d, J=9.5 Hz).

Example 25

N-(5-Chloroquinolin-2-yl)-4-methylbenzenesulfonamide

The title compound was obtained from 2-amino-5-chloroquinoline(Preparation Example 2) and 4-toluenesulfonyl chloride by the procedureof Example 1.

¹H-NMR(CDCl₃) δ (ppm): 2.41(3H, s), 6.98(1H, d, J=9.3 Hz), 7.28(2H, d,J=8.2 Hz), 7.35(1H, d, J=7.9 Hz), 7.41(1H, d, J=7.9 Hz), 7.53(1H, t,J=7.9 Hz), 7.88(2H, d, J=8.2 Hz), 8.26(1H, d, J=9.3 Hz)

Example 26

N-(5-Chloroquinolin-2-yl)-4-sulfamoylbenzenesulfonamide

The title compound was obtained from 2-amino-5-chloroquinoline(Preparation Example 2) and 4-sulfamoylbenzenesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(CDCl₃) δ (ppm): 7.42-7.49(3H, m), 7.58(1H, t, J=8.0 Hz),8.00-8.12(4H, m,), 8.39(1H, d, J=9.3 Hz).

Example 27

N-(5-Bromoquinolin-2-yl)-4-(N-ethylsulfamoyl)benzenesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Preparation Example 2) and 4-(N-ethylsulfamoyl)benzenesulfonyl chlorideby the procedure of Example 1.

¹H-NMR(CDCl₃) δ (ppm): 1.14(3H, t, J=7.5 Hz), 3.01-3.09(2H, m), 7.08(1H,d, J=9.5 Hz), 7.42(1H, dd, J=7.6 Hz, 1.3 Hz), 7.49(1H, t, J=7.6Hz),7.65(1H, dd, J=7.6 Hz, 1.3 Hz), 7.96(2H, d, J=8.7 Hz), 8.10(2H, d,J=8.7 Hz), 8.31(1H, d, J=9.5 Hz).

Example 28

3-(Cyano-N-(8-chloroquinolin-3-yl)-benzenesulfonamide

The title compound was obtained from 3-amino-8-chloroquinoline(Preparation Example 9) and 3-cyanobenzenesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(CDCl₃) δ (ppm): 7.52(1H, t, J=7.9 Hz), 7.59(1H, t, J=7.9 Hz),7.72-7.86(3H, m, ), 8.00(1H, d, J=7.9 Hz), 8.13(1H, d, J=3.2 Hz),8.16(1H, s, ), 8.64(1H, d, J=3.2 Hz).

Example 29

N-(8-Chloroquinolin-3-yl)-3-methylbenzenesulfonamide

The title compound was obtained from 3-amino-8-chloroquinoline(Preparation Example 9) and 3-toluenesulfonyl chloride by the procedureof Example 1.

¹H-NMR(CDCl₃) δ (ppm): 2.35(3H, s), 7.16-7.79(7H, m), 8.09(1H, d, J=2.7Hz), 8.65(1H, d, J=2.7 Hz).

Example 30

N-(8-Chloroquinolin-3-yl)-3-sulfamoylbenzenesulfonamide

The title compound was obtained from 3-amino-8-chloroquinoline(Preparation Example 9) and 3-sulfamoylbenzenesulfonyl chloride by theprocedure of Example 1.

¹H-NMR(CDCl₃) δ (ppm): 7.46(1H, t, J=7.6 Hz), 7.53(1H, t, J=7.6 Hz),7.58-7.78(2H, m, ), 8.00(1H, d, J=7.6 Hz), 8.04(1H, d, J=7.6 Hz),8.14(1H, d, J=2.8 Hz) 8.47(1H, s), 8.59(1H, d, J=2.8 Hz).

Example 31

N-(8-Methylquinolin-3-yl)-3-pyridinesulfonamide

White crystals (562 mg) were obtained in the same manner as in Example1, except using 1.02 g (5.2 mmol) of 7-amino-2-chloro-4-methylquinoline(Preparation Example 16) and 0.9 g (5.2 mmol) of 3-pyridinesulfonylchloride. To 102 mg (0.29 mmol) of the white crystals were addedmethanol (4 ml), tetrahydrofuran (4 ml) and 10% palladium-carbon (5 mg),followed by stirring in hydrogen atmosphere for 6 hours. The reactionmixture was filtrated through Celite and then evaporated. The residuewas washed with ethyl acetate, to give 65 mg of the title compound.

¹H-NMR(DMSO-d₆) δ (ppm): 2.82(3H, s), 7.64-7.66(2H, m), 7.73(1H, d,J=5.2 Hz), 8.03(1H, s), 8.30-8.35(2H, m), 8.82(1H, dd, J=1.2, 4.8 Hz),9.00(1H, d, J=5.2 Hz), 9.11(1H, d, J=2.0 Hz).

Example 32

N-(8-Methylquinolin-3-yl)-4-cyanobenzenesulfonamide

White crystals (358 mg) were obtained in the same manner as in Example1, except using 305 mg (1.58 mmol) of 7-amino-2-chloro-4-methylquinoline(Preparation Example 16) and 0.48 g (2.4 mmol) of 4-cyanobenzenesulfonylchloride. To the white crystals (140 mg, 0.38 mmol) were added aceticacid (6 ml), water (2 ml) and zinc (122 mg), followed by stirring at 60degrees for 15 minutes. The reaction mixture was filtered through Celiteand then an aqueous saturated sodium hydrogencarbonate was addedthereto, followed by extracting with ethyl acetate. The organic layerwas washed with brine, dried over magnesium sulfate and concentrated.Then, the residue was purified by silica gel chromatography, to give 82mg of the title compound.

¹H-NMR(DMSO-d₆) δ (ppm): 2.60(3H, s), 7.26(1H, dd, J=1.2, 4.4 Hz),7.41(1H, dd, J=2.4, 8.8 Hz), 7.64(1H, d, J=2.4 Hz), 7.97-8.06(1H, m),7.98(2H, d, J=8.4 Hz), 8.04(2H, d, J=8.4 Hz), 8.66(1H, d, J=4.4 Hz),11.06(1H, s).

Example 33

N-(6-(6-Chloro-8-cyanoquinolin-3-yl)-3-pyridinesulfonamide

White crystals (764 mg) were obtained in the same manner as in Example1, except using 3.0 g (13 mmol) of ethyl7-amino-2-chloroquinoline-4-carboxylate (Preparation Example 13) and 2.3g (13 mmol) of 3-pyridinesulfonyl chloride. To a solution of 108 mg(0.28 mmol) of the prepared crystals in ethanol (6 ml) was added 1 Nsodium hydroxide (0.5 ml), followed by stirring overnight. To thereaction mixture was added 1 N hydrochloric acid, followed by extractingtwice with ethyl acetate. The organic layer was washed with brine, driedover magnesium sulfate and concentrated, to give the residue. To asolution of the residue in tetrahydrofuran (10 ml) were added oxalylchloride (0.04 ml) and one drop of dimethylformamide under ice-cooling,followed by stirring at room temperature for 30 minutes. After 30minutes, a saturated ammonium aqueous solution (5 ml) was added thereto,followed by stirring for further 10 minutes. To the reaction mixture wasadded brine, followed by extracting with ethyl acetate. The organiclayer was dried over magnesium sulfate and concentrated, to give theresidue. To a solution of the residue in tetrahydrofuran (6 ml) wereadded pyridine (0.06 ml) and trifluoroacetic anhydride (0.05 ml) underice-cooling, followed by stirring at room temperature for 30 minutes. Tothe reaction mixture was added brine, followed by extracting with ethylacetate. The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by silica gel chromatography, togive 37 mg of the title compound.

¹H-NMR(DMSO-d₆) δ (ppm): 7.62-7.66(1H, m), 7.68-7.72(2H, m), 8.08(1H, d,J=8.8 Hz), 8.23(1H, s), 8.26-8.29(1H, m), 8.81(1H, dd, J=1.6, 4.8 Hz),9.04(1H, d, J=2.4 Hz).

Example 34

N-(8-Chloroquinolin-3-yl)-4-cyanobenzenesulfonamide

The title compound (58 mg) was obtained by the procedure of Example 1,except using 38 mg (0.21 mmol) of 3-amino-8-chloroquinoline (PreparationExample 9) and 43 mg (0.21 mmol) of 4-cyanobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆)δ (ppm): 7.55(1H, t, J=7.6 Hz), 7.84(1H, d, J=7.6 Hz),7.95(1H, t, J=7.6 Hz), 7.99(2H, d, J=8.8 Hz), 8.04(2H, d, J=8.8 Hz),8.09(1H, d, J=2.8 Hz), 8.73(1H, d, J=2.8 Hz), 11.39(1H, s).

Example 35

N-(8-Chloroquinolin-3-yl1)-4-(N-ethylsulfamoyl)benzenesulfonamide

The title compound (36 mg) was obtained in the same manner as in Example1, except using 36 mg (0.19 mmol) of 3-amino-8-chloroquinoline(Preparation Example 9) and 52 mg (0.19 mmol) of4-(N-ethylsulfamoyl)benzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 0.84(3H, t, J=7.2 Hz), 2.78-2.71(2H, m),7.54(1H, t, J=7.6 Hz), 7.77(1H, t, J=6.0 Hz), 7.83(1H, t, J=7.6 Hz),7.92-7.95(1H, m), 7.93(2H, d, J=8.8 Hz), 8.03(2H, d, J=8.8 Hz), 8.07(1H,d, J=2.4 Hz), 8.73(1H, d, J=2.4 Hz), 11.20(1H, s).

Example 36

N-(8-Chloroquinolin-3-yl)-3-pyridinesulfonamide

The title compound (29 mg) was obtained by the procedure of Example 1,except using 33 mg (0.19 mmol) of 3-amino-8-chloroquinoline (PreparationExample 9) and 33 mg (0.19 mmol) of 3-pyridinesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 7.54(1H, t, J=7.6 Hz), 7.60(1H, dd, J=4.8, 7.6Hz), 7.81(1H, d, J=7.6 Hz), 7.94(1H, d, J=7.6 Hz), 8.09(1H, d, J=2.8Hz), 8.19-8.26(1H, m), 8.72(1H, d, J=2.8 Hz), 8.77(1H, d, J=1.6, 4.8Hz), 9.00(1H, d, J=2.8 Hz), 11.46(1H, s).

Example 37

N-(8-Chloroquinolin-3-yl)-5-ethylsulfamoyl-2-pyridinesulfonamide

The title compound (10 mg) was obtained by the procedure of Example 1,except using 30 mg (0.17 mmol) of 3-amino-8-chloroquinoline (PreparationExample 9) and 95 mg (0.34 mmol) of5-ethylsulfamoyl-2-chlorosulfonylpyridine.

¹H-NMR(DMSO-d₆) δ (ppm): 0.88(3H, t, J=7.6 Hz), 2.79-2.86(2H, m),7.55(1H, t, J=7.6 Hz), 7.85(1H, t, J=7.6 Hz), 7.94(1H, d, J=7.6 Hz),8.00(1H, t, J=6.4 Hz), 8.16(1H, d, J=2.8 Hz), 8.27(1H, d, J=8.0 Hz),8.41(1H, d, J=2.4, 8.0 Hz), 8.84(1H, d, J=2.8 Hz), 9.04(1H, d, J=2.4Hz), 11.47(1H, s).

Example 38

N-(8-Trifluoromethylquinolin-3-yl)-4-cyanobenzenesulfonmide

The title compound (59 mg) was obtained by the procedure of Example 1,except using 35 mg (0.17 mmol) of 3-amino-8-trifluoromethylquinoline(Preparation Example 10) and 37 mg (0.18 mmol) of 4-cyanobenzenesulfonylchloride.

¹H-NMR(DMSO-d₆) δ (ppm): 7.71(1H, t, J=7.6 Hz), 8.03-8.09(5H, m),8.19(1H, d, J=2.4 Hz), 8.30(1H, d, J=7.6 Hz), 8.78(1H, d, J=2.4 Hz),11.72(1H, s).

Example 39

N-(8-Trifluoromethylquinolin-3-yl)-4-(N-ethylsulfamoyl)benzenesulfonamide

The title compound (60 mg) was obtained by the procedure of Example 1,except using 35 mg (0.17 mmol) of 3-amino-8-trifluoromethylquinoline(Preparation Example 10) and 56 mg (0.20 mmol) of4-(N-ethylsulfamoyl)benzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 0.83(3H, t, J=7.2 Hz), 2.71-2.78(2H, m),7.69(1H, t, J=8.0 Hz), 7.76(1H, t, J=5.6 Hz), 7.93(1H, d, J=8.8 Hz),8.04-8.07(3H, m), 8.13(1H, d, J=2.8 Hz), 8.25(1H, d, J=8.0 Hz), 8.75(1H,d, J=2.8 Hz), 11.28(1H, s).

Example 40

N-(8-Trifluoromethylquinolin-3-yl)-3-pyridinesulfonamide

The title compound (71 mg) was obtained by the procedure of Example 1,except using 45 mg (0.21 mmol) of 3-amino-8-trifluoromethylquinoline(Preparation Example 10) and 45 mg (0.25 mmol) of 3-pyridinesulfonylchloride.

¹H-NMR(DMSO-d₆) δ (ppm): 7.59-7.63(1H, m), 7.70(1H, t, J=7.6 Hz),8.06(1H, d, J=7.6 Hz), 8.20(1H, d, J=2.8 Hz), 8.23-8.24(1H, m), 8.30(1H,d, J=7.6 Hz), 8.76(1H, d, J=2.8 Hz), 8.79(1H, dd, J=1.6, 4.8 Hz),9.03(1H, d, J=2.0 Hz), 11.64(1H, s).

Example 41

N-(8-Chloroquinolin-3-yl)-1,2,3,4-tetrahydro-6-naphthalenesulfonamide

The title compound (46 mg) was obtained by the procedure of Example 1,except using 33 mg (0.19 mmol) of 3-amino-8-chloroquinoline (PreparationExample 9) and 73 mg (0.22 mmol) of6-chlorosulfonyl-1,2,3,4-tetrahydronaphthalene.

¹H-NMR(DMSO-d₆) δ (ppm): 1.68(4H, br), 2.71(4H, br), 7.20(1H, t, J=8.4Hz), 7.52(1H, t, J=7.6 Hz), 7.53(1H, dd, J=2.0, 8.4 Hz), 7.58(1H, d,J=2.0 Hz), 7.80(1H, d, J=7.6 Hz), 7.93(1H, d, J=7.6 Hz), 8.06(1H, d,J=2.4 Hz), 8.73(1H, d, J=2.4 Hz), 10.94(1H, s).

Example 42

N-(8-Chloroquinolin-3-yl)-2,3-dihydro-9-benzofuransulfonamide

The title compound (57 mg) was obtained by the procedure of Example 1,except using 30 mg (0.17 mmol) of 3-amino-8-chloroquinoline (PreparationExample 9) and 44 mg (0.20 mmol) of5-chlorosulfonyl-2,3-dihydrobenzofuran.

¹H-NMR(DMSO-d₆) δ (ppm): 3.19(2H, t, J=8.8 Hz), 4.58(2H, t, J=8.8 Hz),6.86(1H, d, J=8.8 Hz), 7.23(1H, t, J=7.6 Hz), 7.62(1H, dd, J=1.6, 8.8Hz), 7.72(1H, d, J=1.6 Hz), 7.80(1H, d, J=7.6 Hz), 7.92(1H, d, J=7.6Hz), 8.03(1H, d, J=2.4 Hz), 8.73(1H, d, J=2.4 Hz), 10.85(1H, s).

Example 43

N-(8-Chloro-4-vinylquinolin-3-yl)-4-cyanobenzenesulfonamide

The title compound (15 mg) was obtained by the procedure of Example 1,except using 30 mg (0.15 mmol) of 3-amino-4-vinyl-8-chloroquinoline(Preparation Example 12) and 36 mg (0.18 mmol) of 4-cyanobenzenesulfonylchloride.

¹H-NMR(DMSO-d₆) δ (ppm): 5.29(1H, d, J=17.6 Hz), 5.59(1H, d, J=11.6 Hz),6.75(1H, dd, J=11.6, 17.6 Hz), 7.59(1H, t, J=8.0 Hz), 7.80(2H, dd, J=8.8Hz), 7.96(1H, d, J=8.0 Hz), 8.00-8.04(3H, m), 8.74(1H, s), 10.58(1H, s).

Example 44

N-(8-Trifluoromethylquinolin-3-yl)-5-(N-acetylindoline)sulfonamide

The title compound (186 mg) was obtained by the procedure of Example 1,except using 109 mg (0.51 mmol) of 3-amino-8-trifluoromethylquinoline(Preparation Example 10) and 200 mg (0.77 mmol) of5-chlorosulfonyl-N-acetylindoline.

¹H-NMR(DMSO-d₆) δ (ppm): 2.13(3H, s), 3.14(2H, t, J=8.0 Hz), 4.09(2H, t,J=8.8 Hz), 7.67(1H, t, J=8.4 Hz), 7.69-7.73(2H, m), 8.01(1H, d, J=7.2Hz), 8.07-8.09(2H, m), 8.24(1H, d, J=8.4 Hz), 8.73(1H, d, J=2.8 Hz),10.98(1H, s).

Example 45

N-(8-Bromoquinolin-3-yl)-2-methylthio-5-pyridinesufonamide

White crystals (197 mg, 0.556 mmol) were obtained in the same manner asin Example 1, except using 100 mg (0.56 mmol) of3-amino-8-bromoquinoline (Preparation Example 5) and 142 mg (0.67 mmol)of 2-chloro-5-pyridinesulfonyl chloride. To the crystals (60 mg, 0.17mmol) were added dimethylformamide (1 ml), pyridine (1 ml) and sodiumthiomethoxide (111 mg, 1.6 mmol), followed by stirring at roomtemperature for 3 hours. TO the reaction mixture was added brine,followed by extracting with ethyl acetate. The organic layer was driedover magnesium sulfate and concentrated. The resulting residue waspurified by silica gel chromatography, to give 62 mg of the titlecompound.

¹H-NMR(DMSO-d₆) δ (ppm): 3.33(3H, s), 7.47(1H, d, J=8.8 Hz), 7.55(1H, t,J=8.0 Hz), 7.84(1H, d, J=6.8 Hz), 7.97(1H, d, J=8.8 Hz), 7.98(1H, d,J=8.8 Hz), 8.13(1H, d, J=2.0 Hz), 8.74(1H, d, J=2.4 Hz), 8.82(1H, d,J=2.0 Hz), 11.16(1H, s).

Example 46

N-(8-Bromoquinolin-3-yl)-4-(2-methylsulfonylethyl)benzenesulfonamide

The title compound (55 mg) was obtained by the procedure of Example 1,except using 30 mg (0.13 mmol) of 3-amino-8-bromoquinoline (PreparationExample 5) and 57 mg (0.20 mmol) of4-(2-methylsulfonylethyl)benzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 2.92(3H, s), 3.00-3.05(2H, m), 3.37-3.44(2H,m), 7.46(1H, t, J=7.6 Hz), 7.48(2H, d, J=8.0 Hz), 7.80(2H, d, J=8.0 Hz),7.96(1H, d, J=7.6 Hz), 7.99(1H, d, J=7.6 Hz), 8.04(1H, d, J=2.4 Hz),8.71(1H, d, J2.4 Hz), 11.02(1H, s).

Example 47

N-(8-Bromoquinolin-3-yl) -4-oxa-7-thiochromansulfonamide

The title compound (99 mg) was obtained by the procedure of Example 1,except using 51 mg (0.23 mmol) of 3-amino-8-bromoquinoline (PreparationExample 5) and 86 mg (0.34 mmol) of7-chlorosulfonyl-4-oxa-benzothiochroman.

¹H-NMR(DMSO-d₆) δ (ppm): 3.18(2H, t, J=8.4 Hz), 4.39(2H, t, J=8.4 Hz),6.92(1H, d, J=8.8 Hz), 7.42(1H, dd, J=2.4, 8.8 Hz), 7.46(1H, t, J=7.6Hz), 7.59(1H, d, J=2.4 Hz), 7.99(1H, d, J=7.6 Hz), 8.02(1H, d, J=7.6Hz), 8.05(1H, br), 8.71(1H, d, J=2.4 Hz), 10.92(1H, s).

Example 48

N-(8-Bromoquinolin-3-yl)-4-(2-acetamideethyl)benzenesulfonamide

The title compound (56 mg) was obtained by the procedure of Example 1,except using 30 mg (0.13 mmol) of 3-amino-8-bromoquinoline (PreparationExample 5) and 201 mg (0.77 mmol) ofN-(4-chlorosulfonylphenethyl)acetamide.

¹H-NMR(DMSO-d₆) δ (ppm): 2.71(2H, t, J=7.2 Hz), 3.25-3.20(2H, m),7.37(2H, d, J=8.4 Hz), 7.46(1H, t, J=8.0 Hz), 7.78(2H, d, J=8.4 Hz),7.86(1H, br), 7.97(1H, d, J=8.0 Hz), 8.00(1H, d, J=8.0 Hz), 8.04(1H, d,J=2.8 Hz), 8.72(1H, d, J=2.8 Hz), 10.99(1H, s).

Example 49

N-(8-Bromoquinolin-3-yl)-1,2,3,4-tetrahydro-N-acetyl-7-isoquinolinesulfonamide

White crystals (180 mg) were obtained in the same manner as in Example1, except using 145 mg (0.65 mmol) of 3-amino-8-bromoquinoline(Preparation Example 5) and 277 mg (0.85 mmol) of1,2,3,4-tetrahydro-2-(trifluoroacetyl)isoquinoline-7-sulfonyl chloride.To the crystals were added ethanol (20 ml) and 1 N sodium hydroxideaqueous solution (0.5 ml), followed by stirring at room temperature for30 minutes. To the reaction mixture was added 1 N hydrochloric acid (0.4ml), followed by extracting with ethyl acetate. The organic layer waswashed with brine, dried over magnesium sulfate and concentrated. To theresulting residue were added pyridine (0.5 ml) and acetic anhydride(0.014 ml), followed by stirring at room temperature for 1 hour. Brinewas added thereto, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by silica gel chromatography, to give 113 mg of thetitle compound.

¹H-NMR(DMSO-d₆) δ (ppm): 1.19-1.28(2H, m), 2.05(3H, s), 2.97(1H, t,J=6.4 Hz), 3.03(1H, t, J=6.4 Hz), 3.75(1H, t, J=6.4 Hz), 4.73(1H, s),7.37(1H, t, J=8.8 Hz), 7.53-7.58(1H, m), 7.75-7.87(2H, m), 7.91(1H, d,J=8.0 Hz), 8.19-8.27(2H, m), 8.76-8.78(1H, m).

Example 50

N-(8-Bromoquinolin-3-yl) -1,1-dioxide-6-yl -sulfonamide

White crystals were obtained in the same manner as in Example 1, exceptusing 71 mg (0.32 mmol) of 3-amino-8-bromoquinoline (Preparation Example5) and 119 mg (0.48 mmol) of 6-chlorosulfonylbenzothiochroman. To thecrystals were added chloroform (10 ml) and m-chloroperbenzoic acid (145mg) under ice-cooling, followed by stirring at room temperature for 1hour. An aqueous saturated sodium thiosulfate was added thereto, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried over magnesium sulfate and concentrated. The residuewas purified by silica gel chromatography, to give 113 mg of the titlecompound.

¹H-NMR(DMSO-d₆) δ (ppm): 2.26-2.29(2H, m), 3.05(2H, t, J=6.0 Hz),3.53-3.56(2H, m), 7.48(1H, t, J=7.6 Hz), 7.86-7.90(2H, m), 7.96-8.04(3H,m), 8.10(1H, d, J=2.4 Hz), 8.75(1H, d, J=2.4 Hz), 11.24(1H, s).

Example 51

N-(8-Bromoquinolin-3-yl)-4-(3-methylsulfonylpropyl)benzenesulfonamide

The title compound (62 mg) was obtained by the procedure of Example 1,except using 33 mg (0.14 mmol) of 3-amino-8-bromoquinoline (PreparationExample 5) and 66 mg (0.22 mmol) of4-(3-methylsulfonylpropyl)benzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 1.90-1.98(2H, m), 2.72(2H, t, J=8.0 Hz),2.93(3H, s), 3.06(2H, t, J=8.0 Hz), 7.42(2H, d, J=8.0 Hz), 7.46(1H, d,J=7.6 Hz), 7.97(2H, d, J=7.6 Hz), 8.00(1H, d, J=7.6 Hz), 8.05(1H, d,J=2.4 Hz), 8.72(1H, d, J=2.4 Hz), 11.01(1H, s).

Example 52

N-(8-Bromoquinolin-3-yl)-4-fluorobenzenesulfonamide

The title compound (50 mg) was obtained by the procedure of Example 1,except using 33 mg (0.14 mmol) of 3-amino-8-bromoquinoline (PreparationExample 5) and 39 mg (0.20 mmol) of 4-fluorobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 7.40(1H, t, J=8.8 Hz), 7.47(1H, t, J=7.6 Hz),7.89-7.93(2H, m), 9.78(1H, dd, J=0.9, 7.6 Hz), 8.01(1H, dd, J=0.9, 7.6Hz), 8.06(1H, d, J=2.4 Hz), 8.71(1H, d, J=2.4 Hz), 11.06(1H, s).

Example 53

N-(8-Bromoquinolin-3-yl)-4-methoxy-2-pyridazinesulfonamide

Under ice-cooling, chlorine gas was blown into a solution of2-benzylthio-5-methoxypyridazine (0.86 g, 3.7 mmol, Preparation Example14) in concentrated hydrochloric acid (8 ml), followed by stirring for 1hour. Then, to the reaction mixture was added ice water, followed byextracting with ethyl acetate. The organic layer was successively washedwith water and brine, dried over magnesium sulfate and concentrated, togive the residue 700 mg (2.1 mmol). The title compound (93 mg) wasobtained by the procedure of Example 1, except using 180 mg (0.54 mmol)of the above-obtained residue and 60 mg (0.27 mmol) of3-amino-8-bromoquinoline (Preparation Example 5).

¹H-NMR(DMSO-d₆) δ (ppm): 4.07(3H, s), 7.44(1H, d, J=9.2 Hz), 7.47(1H, t,J=7.6 Hz), 7.96(1H, t, J=7.6 Hz), 8.02(1H, t, J=7.6 Hz), 8.13(1H, d,J=2.4 Hz), 8.17(1H, d, J=9.2 Hz), 8.82(1H, d, J=2.4 Hz), 11.54(1H, s).

Example 54

N-(8-Bromoquinolin-3-yl)-benzenesulfonamide

The title compound (49 mg) was obtained by the procedure of Example 1,except using 30 mg (0.13 mmol) of 3-amino-8-bromoquinoline (PreparationExample 5) and 35 mg (0.20 mmol) of benzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 7.45(1H, d, J=7.6 Hz), 7.53-7.63(3H, m),7.84-7.86(2H, m), 7.96(1H, dd, J=1.2, 7.6 Hz), 7.99(1H, dd, J=1.2, 7.6Hz), 8.04(1H, d, J=2.8 Hz), 8.71(1H, d, J=2.8 Hz), 11.02(1H, s).

Example 55

N-(8-Bromoquinolin-3-yl)-4-carboxamide-2-pyridinesulfonamide

Under ice-cooling, chlorine gas was blown into a solution of2-benzylthio-4-carboxamidopyridine (1.1 g, 4.3 mmol, Preparation Example15) in concentrated hydrochloric acid (16 ml), followed by stirring for1 hour. Then, to the reaction mixture was added to ice water, followedby extracting with ethyl acetate. The organic layer was successivelywashed with water and brine, dried over magnesium sulfate andconcentrated. The title compound (37 mg) was obtained by the procedureof Example 1, except using 140 mg (0.40 mmol) of the above-obtainedresidue and 45 mg (0.20 mmol) of 3-amino-8-bromoquinoline.

¹H-NMR(DMSO-d₆) δ (ppm): 7.46(1H, d, J=8.0 Hz), 7.94-7.96(2H, m),8.00-8.02(2H, m), 8.12(1H, d, J=2.4 Hz), 8.44(1H, br), 8.49(1H, br),8.83-8.85(2H, m), 11.35(1H, s).

Example 56

N-(8-Bromoquinolin-3-yl)-3-methoxybenzenesulfonamide

The title compound (70 mg) was obtained by the procedure of Example 1except using 40 mg (0.18 mmol) of 3-amino-8-bromoquinoline (PreparationExample 5) and 56 mg (0.27 mmol) of 3-methoxybenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 3.76(3H, s), 7.17(1H, dd, J=2.8, 8.0 Hz),7.34-7.40(2H, m), 7.45(1H, t, J=7.6 Hz), 7.46(1H, t, J=7.6 Hz), 7.99(2H,t, J=7.6 Hz), 8.07(1H, d, J=2.4 Hz), 8.72(2H, m), 11.35(1H, d, J=2.4 Hz)

Example 57

N-(8-Bromoquinolin-3-yl)-3-hydroxybenzenesulfonamide

The title compound (73 mg) was obtained by the procedure of Example 1,except using 45 mg (0.20 mmol) of 3-amino-8-bromoquinoline (PreparationExample 5) and 117 mg (0.61 mmol) of 3-hydroxybenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 6.97(1H, d, J=8.0 Hz), 7.18(1H, br), 7.25(1H,d, J=8.0 Hz), 7.34(1H, t, J=8.0 Hz), 7.47(1H, t, J=8.0 Hz), 7.97(1H, d,J=8.0 Hz), 8.01(1H, d, J=8.0 Hz), 8.04(1H, d, J=2.4 Hz), 8.73(1H, d,J=2.4 Hz), 10.15(1H, s), 10.96(1H, s).

Example 58

N-(4-Bromoisoquinolin-7-yl) -4-chlorobenzenesulfonamide

In 1.5 ml of pyridine was dissolved 20 mg (0.09 mmol) of7-amino-4-bromoisoquinoline (Preparation Example 20), 23 mg of4-chlorobenzenesulfonyl chloride was added thereto, followed by stirringat room temperature overnight. To the reaction mixture was added water,followed by extracting with ethyl acetate. The extract was dried overmagnesium sulfate and concentrated. Then, the resulting residue waspurified by silica gel thin layer chromatography, to give 13 mg of thetitle compound. Melting point: gradually decomposed from 229 degrees.

¹H-NMR(DMSO-d₆) δ (ppm): 7.59-7.61(2H, m), 7.66(1H, dd, J=2 Hz, 9.2 Hz),7.82-7.84(3H, m), 7.99(1H, d, J=9.2 Hz), 8.60(1H, s).

Example 59

N-(4-Bromoisoquinolin-7-yl)-6-chloro-3-pyridinesulfonamide

The title compound was obtained from 7-amino-4-bromo isoquinoline(Preparation Example 20) and 6-chloro-3-pyridinesulfonyl chloride in thesame manner as in Example 58.

¹H-NMR(DMSO-d₆) δ (ppm): 7.66(1H, dd, J=2.4 Hz, 9.2 Hz), 7.70(1H, d,J=8.4 Hz), 7.89(1H, d, J=2.4 Hz), 8.02(1H, d, J=9.2 Hz), 8.20(1H, dd,J=2.4 Hz, 8.4 Hz), 8.64(1H, s), 8.84(1H, d, J=2.4 Hz), 9.26(1H, s).

Example 60

2-(4-(Chlorobenzenesulfonylamino)-1,6-naphthylidine

In dichloromethane (6.0 ml) was dissolved 200 mg of2-amino-1,6-naphthyridine (Preparation Example 25), and triethylamine(0.20 ml) and 4-chlorobenzenesulfonyl chloride (0.31 g) were addedthereto, followed by stirring at 40° C. for 1.5 hours. An aqueoussaturated sodium bicarbonate was added thereto, followed by extractingwith ethyl acetate. The extract was washed with brine, dried overanhydrous magnesium sulfate and the solvent was evaporated. The residuewas purified by silica gel column, to give the title compound (84 mg,21.44%) as pale yellow crystals.

¹H-NMR(CDCl₃) δ (ppm): 7.10(1H, d, J=9.2 Hz), 7.37(1H, d, J=5.4 Hz),7.46(2H, d, J=8.8 Hz), 7.93(2H, d, J=8.8 Hz), 8.94(1H, d, J=9.2 Hz),8.66(1H, d, J=5.4 Hz), 8.92(1H, brs).

Example 61

1-Chloro-6-(4-cyanobenzenesulfonylamino)isoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-chloroisoquinoline (Preparation Example 23) and4-cyanobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 7.52(1H, dd, J=2.0, 8.8 Hz), 7.68(1H, d, J=2.0Hz), 7.79(1H, d, J=5.6 Hz), 8.03(4H, m), 8.18(1H, d, J=5.6 Hz), 8.21(1H,d, J=8.8 Hz), 11.36(1H, s).

Example 62

1-Chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-chloroisoquinoline (Preparation Example 23) and4-chlorobenzenesulfonyl chloride.

¹H-NMR(CDCl₃) δ (ppm): 7.33(1H, brs), 7.39(1H, dd, J=2.0, 8.8 Hz),7.44(2H, d, J=8.8 Hz), 7.50(1H, d, J=5.6 Hz), 7.58(1H, d, J=2.0 Hz),7.81(2H, d, J=8.8 Hz), 8.24(1H, d, J=5.6 Hz), 8.25(1H, d, J=8.8 Hz).

FAB-MS: 353.

Example 63

1-Chloro-6-(4-(pyrrolidin-1-ylsulfonyl)benzenesulfonylamino)isoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-chloroisoquinoline (Preparation Example 23) and4-(pyrrolidin-1-ylsulfonyl)benzenesulfonyl chloride.

¹H-NMR(CDCl₃) δ (ppm): 1.71(4H, m), 3.20(4H, t, J=7.0 Hz), 7.46(1H, d,J=5.4 Hz), 7.49(1H, dd, J=2.0, 9.2 Hz), 7.61(1H, d, J=2.0 Hz), 7.87(2H,d, J=8.8 Hz), 8.02(2H, d, J=8.8 Hz), 8.19(1H, d, J=9.2 Hz), 8.20(1H, d,J=5.4 Hz), 9.72(1H, s).

Example 64

1-Chloro-6-(4-(N-ethylsulfamoyl)benzenesulfonylamino)isoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-chloroisoquinoline (Preparation Example 23) and4-(N-ethylsulfamoyl)benzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 0.81(3H, t, J=7.2 Hz), 2.73(2H, m), 7.53(1H, d,J=9.2 Hz), 7.67(1H, s), 7.75(1H, d, J=6.0 Hz), 7.78(1H, d, J=6.0 Hz),7.92(2H, d, J=8.0 Hz).

Example 65

1-Methoxy-6-(pyridin-3-ylsulfonylamino)isoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) and3-pyridinesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 4.09(3H, s), 7.09(1H, d, J=6.0 Hz), 7.25(1H,dd, J=2.0, 8.8 Hz), 7.37(1H, d, J=8.0, 8.8 Hz), 7.48(1H, d, J=2.0 Hz),7.96(1H, d, J=6.0 Hz), 8.07(1H, ddd, J=1.6, 2.0, 8.0 Hz), 8.14(1H, d,J=8.8 Hz), 8.74(1H, dd, J=1.6, 8.8 Hz), 9.08(1H, d, J=2.0 Hz).

ESI-MS: 316.0.

Example 66

6-(4-Cyanobenzenesulfonylamino)-1-methoxyisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) and4-cyanobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 3.97(3H, s), 7.25(1H, d, J=5.6 Hz), 7.32(1H, d,J=8.8 Hz), 7.51(1H, s), 7.90(1H, d, J=5.6 Hz), 7.97(2H, d, J=7.6 Hz),8.01(2H, d, J=7.6 Hz), 8.03(1H, d, J=8.8 Hz).

Example 67

6-(4-Carbamoylbenzenesulfonylamino)-1-methoxyisoquionline

The title compound was obtained according to the procedure described inSynthesis, 949 (1989), except using6-(4-cyanobenzenesulfonylamino)-1-methoxyisoquinoline (Example 66).

¹H-NMR(DMSO-d₆) δ (ppm): 3.96(3H, s), 7.24(1H, d, J=6.4 Hz), 7.33(1H, d,J=9.2 Hz), 7.51(1H, s), 7.55(1H, brs), 7.88(1H, d, J=6.4 Hz), 7.89(2H,d, J=8.0 Hz), 7.93(2H, d, J=8.0 Hz), 8.01(1H, d, J=9.2 Hz), 8.06(1H,brs), 10.95(1H, s).

FAB-MS: 358.

Example 68

6-(4-(N-Ethylsufamoyl)benzenesulfonylamino)-1-methoxyisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) and4-(N-ethylsulfamoyl)benzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 0.81(3H, t, J=6.8 Hz), 2.71(2H, m), 3.96(3H,s), 7.23(1H, d, J=6.4 Hz), 7.32(1H, d, J=8.8 Hz), 7.48(1H, s), 7.73(1H,brs), 7.89(2H, d, J=8.0 Hz), 7.90(1H, d, J=6.4 Hz), 8.01(3H, m),11.03(1H, brs).

ESI MS: 422.0.

Example 69

6-(2-Aminopyridin-5-ylsulfonylamino)-1-methoxyisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) and6-amino-3-pyridinesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 3.96(3H, s), 6.39(1H, d, J=8.8 Hz), 6.89(2H,s), 7.25(1H, d, J=4.2 Hz), 7.32(1H, d, J=9.2 Hz), 7.47(1H, s), 7.64(1H,d, J=9.2 Hz), 7.89(1H, d, J=4.2 Hz), 8.01(1H, d, J=8.8 Hz), 8.31(1H, s),10.95(1H, s).

ESI MS: 331.0.

Example 70

1-Methoxy-6-(4-methylbenzenesulfonylamino)isoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) and4-toluenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 2.28(3H, s), 3.96(3H, s), 7.22(1H, d, J=6.0Hz), 7.32(3H, m), 7.48(1H, s), 7.71(2H, d, J=8.4 Hz), 7.88(1H, d, J=6.0Hz), 8.00(1H, d, J=9.2 Hz), 10.79(1H, s).

ESI MS: 329.0.

Example 71

6(4-Acetylaminobenzenesulfonylamino)-1-methoxyisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) and4-acetamidobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 2.01(3H, s), 3.96(3H, s), 7.23(1H, d, J=6.0Hz), 7.32(1H, d, J=9.2 Hz), 7.47(1H, s), 7.67(2H, d, J=8.8 Hz), 7.76(2H,d, J=8.8 Hz), 7.88(1H, d, J=6.0 Hz), 8.00(1H, d, J=9.2 Hz), 10.26(1H,s), 10.75(1H, s).

EST MS: 372.1.

Example 72

6-(4-Methanesulfonylaminobenzenesulfonylamino)-1-methoxyisoquinoline

The nitro group of the compound synthesized in the same manner as inExample 1, except using 6-amino-1-methoxyisoquinoline (PreparationExample 43) and 4-nitrobenzenesulfonyl chloride was reduced in the samemanner as in Preparation Example 170. The resulting compound wasdissolved in pyridine, and under ice-cooling, methanesulfonyl chloridewas added thereto, followed by stirring as it was for 4 hours. Brine wasadded thereto, followed by extracting with ethyl acetate, The extractwas washed with brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated. Then, the residue was purified by silica gelcolumn, and the resulting crystals were recrystallized from ethanol, togive the title compound.

¹H-NMR(DMSO-d₆) δ (ppm): 3.06(3H, s), 3.97(3H, s), 7.24(3H, m), 7.33(1H,d, J=9.0 Hz), 7.49(1H, s), 7.79(2H, d, J=8.8 Hz), 7.89(1H, d, J=6.0 Hz),8.01(1H, d, J=9.0 Hz), 10.39(1H, s), 10.80(1H, s).

ESI MS: 372.1.

Example 73

6-(2-Chloropyridin-5-ylsulfonylamino)-1-methoxyisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) and6-chloro-3-pyridinesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 3.31(3H, s), 3.99(3H, s), 7.30(1H, d, J=6.0Hz), 7.34(1H, d, J=8.8 Hz), 7.56(1H, s), 7.71(1H, d, J=8.8 Hz), 7.92(1H,d, J=6.0 Hz), 8.06(1H, d, J=8.8 Hz), 8.19(1H, d, J=8.8 Hz), 11.13(1H,s).

ESI MS: 350.1.

Example 74

1-Methoxy-6-(3-methylbenzenesulfonylamino)isoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) and3-toluenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 2.31(3H, s), 3.96(3H, s), 7.22(1H, d, J=6.0Hz), 7.32(1H, dd, J=2.0, 8.8 Hz), 7.39(2H, m), 7.47(1H, d, J=2.0 Hz),7.62(1H, m), 7.67(1H, s), 7.87(1H, d, J=6.0 Hz), 8.00(1H, d, J=8.8 Hz),10.84(1H, s).

Example 75

6-Benzylsulfonylamino-1-methoxyisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) andbenzylsulfonyl chloride.

¹H-NMR(CDCl₃) δ (ppm): 4.13(3H, s), 4.42(2H, s), 6.69(1H, brs), 7.13(2H,m), 7.22(2H, m), 7.30-7.37(3H, m), 7.50(1H, d, J=2.4 Hz), 7.99(1H, d,J=6.0 Hz), 8.20(1H, d, J=8.8 Hz).

Example 76

6-(3-Cyanobenzenesulfonylamino)-1-methoxyisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) and3-cyanobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 3.98(3H, s), 7.28(1H, d, J=6.0 Hz), 7.34(1H,dd, J=2.0, 8.8 Hz), 7.53(1H, d, J=2.0 Hz), 7.75(1H, dd, J=8.0, 8.0 Hz),7.91(1H, d, J=6.0 Hz), 8.04(1H, d, J=8.8 Hz), 8.09(2H, m), 9.29(1H, m),11.05(1H, s).

Example 77

1-Methoxy-6-(4-thiazol-2-ylbenzenesulfonylamino)isoquinoline

The compound (40 mg) obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) and4-iodobenzenesulfonyl chloride, 2-tri-n-butylstannylthiazole (136 mg),tetrakis(triphenylphosphine)palladium(0) (11 mg) were heated underreflux in toluene in nitrogen atmosphere for 1 hour. The solvent wasevaporated and the residue was purified by silica gel column. Theresulting crystals were recrystallized from methanol, to give the titlecompound (20 mg).

¹H-NMR(CDCl₃) δ (ppm): 4.08(3H, s), 6.94(1H, brs), 7.09(1H, d, J=6.0Hz), 7.23(1H, dd, J=2.0, 8.8 Hz), 7.41(1H, d, J=3.6 Hz), 7.45(1H, d,J=2.0 Hz), 7.89(2H, d, J=8.4 Hz), 7.90(1H, d, J=8.6 Hz), 7.95(1H, d,J=6.0 Hz), 7 82(2H, d, J=8.4 Hz), 8.13(1H, d, J=8.8 Hz).

Example 78

6-(4-Chlorobenzenesulfonylamino)-1-methoxyisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methoxyisoquinoline (Preparation Example 43) and4-chlorobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 4.00(3H, s), 7.27(1H, d, J=5.6 Hz), 7.45(1H,dd, J=2.0, 8.8 Hz), 7.53(1H, d, J=2.0 Hz), 7.63(2H, d, J=8.8 Hz),7.85(1H, d, J=8.8 Hz), 7.92(1H, d, J=5.6 Hz), 8.06, (1H, J=8.8 Hz),10.97(1H, s).

Example 79

6-(4-Chlorobenzenesulfonylamino)-1-methylisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-methylisoquinoline (Preparation Example 33) and4-chlorobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 2.76(3H, s), 7.56(1H, d, J=6.0 Hz), 7.52(2H,m), 7.60(2H, d, J=8.8 Hz), 7.82(2H, d, J=8.8 Hz), 8.08(1H, d, J=9.2 Hz),8.20(1H, d, J=6.0 Hz).

ESI-MS: 333.0.

Example 80

6-(4-Chlorobenzenesulfonylamino)-1-ethylisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-1-ethylisoquinoline (Preparation Example 48) and4-chlorobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 1.39(3H, t, J=7.6 Hz), 3.25(2H, q, J=7.6 Hz),7.35(1H, dd, J=2.4, 9.2 Hz), 7.38(1H, d, J=5.6 Hz), 7.41(2H, d, J=8.8Hz), 7.53(1H, d, J=2.4 Hz), 7.81(2H, d, J=8.8 Hz), 8.05(1H, d, J=9.2Hz), 8.37(1H, d, J=5.6 Hz). ESI-MS: 347.0.

Example 81

6-(4-(Chlorobenzenesulfonylamino)-4-methylisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-4-ethylisoquinoline (Preparation Example 66) and4-chlorobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 1.18(3H, t, J=7.2 Hz), 2.85(2H, q, J=7.2 Hz),7.38(1H, d, J=8.8 Hz), 7.60(1H, s), 7.62(2H, d, J=8.0 Hz), 7.82(2H, d,J=8.0 Hz), 8.00(1H, d, J=8.8 Hz), 8.26(1H, s), 8.99(1H, s).

Example 82

6-(4-Chlorobenzenesulfonylamino)-4-methylisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-4-methylisoquinoline (Preparation Example 58) and4-chlorobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 2.43(3H, s), 7.41(1H, d, J=8.8 Hz), 7.56(1H,s), 7.62(2H, d, J=8.8 Hz), 7.85(2H, d, J=8.8 Hz), 7.99(1H, d, J=8.8 Hz),8.26(1H, s), 8.98(1H, s), 11.09(1H, brs).

Example 83

6-(4-Chlorobenzenesulfonylamino)-3-methylisoquinoline

The title compound was obtained by the procedure of Example 1, exceptusing 6-amino-3-methylisoquinoline (Preparation Example 76) and4-chlorobenzenesulfonyl chloride.

¹H-NMR(DMSO-d₆) δ (ppm): 2.53(3H, s), 7.30(1H, d, J=8.8 Hz), 7.45(1H,s), 7.50(1H, s), 7.62(2H, d, J=8.4 Hz), 7.84(2H, d, J=8.4 Hz), 7.93(1H,d, J=8.8 Hz), 9.03(1H, s).

Example 84

6-(4-Chlorobenzenesulfonylamino)-1-cyanoisoquinoline

The compound obtained by the procedure of Example 1, except using6-aminoisoquinoline (0.5 g, Synthesis, 733 (1975) and4-chlorobenzenesulfonyl chloride (0.88 g) was dissolved in chloroform(150 ml). Under ice-cooling, m-chloroperbenzoic acid (0.9 g) was addedthereto, followed by stirring at room temperature overnight. The solventwas evaporated, and the resulting crystals were washed with diethylether, collected by filtration and dried, to give6-(4-chlorobenzenesulfonylamino)isoquinoline-N-oxide (1.072 g). Inacetonitrile (1.5 ml) was dissolved 50 mg of the obtained compound. Tothe mixture were added trimethyl cyanide (0.08 ml) and triethylamine(0.04 ml), followed by heating under reflux for 3.5 hours. Afterevaporating the solvent, the residue was purified by silica gel column,to give the title compound (23 mg, 64%) as yellow crystals.

¹H-NMR(DMSO-d₆) δ (ppm): 7.66(2H, d, J=8.8 Hz), 7.67(1H, dd, J=2.0, 9.2Hz), 7.80(1H, d, J=2.0 Hz), 7.93(2H, d, J=8.8 Hz), 8.17(1H, d, J=9.2Hz), 8.18(1H, d, J=5.6 Hz), 8.59(1H, d, J=5.6 Hz).

ESI-MS: 344.1

Example 85

1-Carbamoyl-6-(4-chlorobenzenesulfonylamino)isoquinoline

The crystals obtained by the procedure described in Synthesis, 949(1989), except using6-(4-chlorobenzenesulfonylamino)-1-cyanoisoquinoline (30 mg, Example 83)was washed with diethyl ether, to give the title compound (26 mg, 82%)as colorless crystals.

¹H-NMR(CDCl₃) δ (ppm): 6.25(1H, brs), 7.35(2H, d, J=8.8 Hz), 7.43(1H,dd, J=2.0, 9.2 Hz), 7.62(1H, d, J=2.0 Hz), 7.66 1H, d, J=6.8 Hz),7.81(2H, d, J=8.8 Hz), 8.04(1H, brs), 8.37(1H, brs), 9.32(1H, d, J=9.2Hz), 9.76(1H, brs).

Example 86

6-(4-Chlorobenzenesulfonylamino)-1-methylaminoisoquinoline

A mixture of 1-chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (50mg, Example 61) and 40% methylamine methanol solution (5.0 ml) washeated in a sealed tube at 130° C. for 18 hours. After standing to cool,an aqueous saturated sodium bicarbonate was added thereto and themixture was extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and the solvent wasevaporated. The residue was purified by silica gel column, to give thetitle compound (28 mg, 52%) as a pale yellow solid.

¹H-NMR(CDCl₃) δ (ppm): 3.14(3H, s), 5.22(1H, brs), 6.89(1H, d, J=6.0Hz), 7.19(1H, dd, J=2.4 Hz, 9.2 Hz), 7.31(1H, d, J=2.4 Hz), 7.40(2H, d,J=8.8 Hz), 7.64(1H, d, J=9.2 Hz), 7.73(2H, d, J=8.8 Hz), 7.98(1H, d,J=6.0 Hz).

Example 87

1-Amino-6-(4-chlorobenzenesulfonylamino)isoquinoline

The Crystals obtained by the procedure described in YAKUGAKU ZASSHI(Journal of the Pharmaceutical Society of Japan), 84, 35 (1964), exceptusing 6-(4-chlorobenzenesulfonylamino)isoquinoline-N-oxide (50 mg,intermediate in Example 83) was washed with diethyl ether and dried, togive the title compound (2 mg) as light brown crystals.

¹H-NMR(DMSO-d₆) δ (ppm): 7.76(1H, d, J=6.0 Hz), 6.93(2H, brs), 7.15(1H,dd, J=2.0, 8.8 Hz), 7.27(1H, d, J=2.0 Hz), 7.59(2H, d, J=8.8 Hz),7.63(1H, d, J=6.0 Hz), 7.80(2H, d, J=8.8 Hz), 9.05(1H, d, J=6.0 Hz).

ESI-MS: 334.1.

Example 88

6-(4-Chlorobenzenesulfonylamino)-1-dimethylaminoisoquinoline

In dimethyl sulfoxide (1 ml) was dissolved 60 mg of1-chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (Example 61). Tothe mixture was added 50% dimethylamine methanol solution (0.04 ml),followed by heating under stirring at 80° C. for 10 hours. Afterstanding to cool, water was added thereto and the mixture was extractedwith ethyl acetate. The extract was washed with brine, dried overanhydrous magnesium sulfate and the solvent was evaporated. The residuewas purified by preparative TLC and solidified from isopropyl ether, togive the title compound (17 mg).

¹H-NMR(DMSO-d₆) δ (ppm): 2.96(6H, s), 7.12(1H, d, J=6.0 Hz), 7.27(1H,dd, J=2,0, 9.2 Hz), 7.45(1H, d, J=2.0 Hz), 7.64(2H, d, J=8.8 Hz),7.85(2H, d, J=8.8 Hz), 7.93(1H, d, J=6.0 Hz), 8.01(1H, d, J=9.2 Hz),10.91(1H, brs).

Example 89

6-(4-Chlorobenzenesulfonylamino)-1-hydroxyisoquinoline

In acetic anhydride (0.75 ml) was dissolved 50 mg of6-(4-chlorobenzenesulfonylamino)isoquinoline-N-oxide (intermediate inExample 83), followed by heated under stirring at 80° C. for 16 hoursand then for 2 hours. After standing to cool, an aqueous saturatedsodium bicarbonate was added thereto and the mixture was extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated. The residue wasdissolved in ethanol (2.0 ml) and water (0.5 ml), followed by heatingunder reflux for 0.5 hour. After evaporating the solvent, the residuewas purified by silica gel column, to give the title compound (20 mg) asa pale red solid.

¹H-NMR(CDCl₃) δ (ppm): 6.58(1H, d, J=7.2 Hz), 7.22(1H, d, J=7.2 Hz),7.31(1H, dd, J=2.0, 8.4 Hz), 7.54(1H, d, J=2.0 Hz), 7.56 (2H, d, J=8.8Hz), 8.01(2H, d, J=8.8 Hz), 8.53(1H, d, J=8.4 Hz), 10.36(1H, brs).

ESI-MS: 335.1.

Example 90

6-(4-Chlorobenzenesulfonylamino)-1-ethoxyisoquinoline

In dimethyl sulfoxide (1 ml) was dissolved 57 mg of1-chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (Example 61). Tothe mixture were added ethanol (0.1 ml) and 60% sodium hydride (14 mg),followed by heating under stirring at 80° C. for 9 hours. After standingto cool, water was added thereto and the mixture was extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated. Then, the residue waspurified by preparative TLC and solidified from isopropyl ether, to givethe title compound (21 mg).

¹H-NMR(DMSO-d₆) δ (ppm): 1.38(3H, t, J=7.2 Hz), 4.46(2H, q, J=7.2 Hz),7.24(1H, d, J=6.0 Hz), 7.35(1H, dd, J=2.0, 9.2 Hz), 7.50(1H, d, J=2.0Hz), 7.63(2H, d, J=8.8 Hz), 7.90(1H, d, J=6.0 Hz), 8.04(1H, d, J=9.2Hz), 10.94(1H, brs).

Example 91

N-(5-Vinylquinolin-2-yl)-3-pyridinesulfonamide

A solution of 2-amino-5-bromoquinoline (510 mg, Preparation Example 1),vinyltributyltin (0.94 ml), toluene (4 ml),tetrakis(triphenylphosphine)palladium(0) (20 mg) and2,6-di-t-butyl-p-cresol (about 0.1 mg) was stirred at 120° C. for 4hours. After cooling to room temperature, water was added thereto andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas dried over sodium sulfate and concentrated. Then, the resultingsolid was washed with hexane, to give 282 mg of a solid containing avinyl derivative. The solid was dissolved in 2 ml of pyridine and 412 mgof 3-pyridinesulfonyl chloride was added thereto, followed by stirringat room temperature overnight. Water was added thereto and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was dried oversodium sulfate and concentrated. Then, the resulting solid was washedwith methanol, to give the title compound (235 mg).

¹H-NMR(CDCl₃) δ (ppm): 5.59(1H, dd, J=10.8 Hz, 1.5 Hz), 5.82(1H, dd,J=16.9 Hz, 1.5 Hz), 6.95(1H, d, J=10.3 Hz), 7.20(1H, dd, J=10.8 Hz, 16.9Hz), 7.36(1H, d, J=8.5 Hz), 7.43(1H, m), 7.50(1H, d, J=8.5 Hz), 7.62(1H,t, J=8.5 Hz), 8.24(1H, d, J=10.3 Hz), 8.29(1H, m), 8.74(1H, m), 9.22(1H,m).

Example 92

N-(4-Trifluoromethylcoumarin-7-yl)-4-chlorobenzenesulfonamide

To a solution of 7-amino-4-trifluoromethylcoumarin (200 mg, 0.87 mmol)and 4-dimethylaminopyridine (1 mg) in pyridine (3 ml) was added4-chlorobenzenesulfonyl chloride (203 mg, 0.96 mmol), followed bystirring at 70 degrees for 50 minutes. To the reaction mixture was added2 N hydrochloric acid, followed by extracting with ethyl acetate. Theorganic layer was washed with water and brine, dried over magnesiumsulfate and evaporated. The resulting residue was crystallized fromethyl acetate-diisopropyl ether, to give 253 mg of the title compound asa pale yellow solid.

¹H-NMR(DMSO-d₆) δ (ppm): 6.87(1H, s), 7.12(1H, d, J=2.4 Hz), 7.17(1H,dd, J=2.6, 8.4 Hz), 7.60(1H, d, J=8.4 Hz), 7.67(2H, d, J=6.8 Hz),7.87(2H, d, J=6.8 Hz), 11.29(1H, s).

TABLE 2-1 Ex. No. Structural Formula 1

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 2-2 Ex. No. Structural Formula 15

16

17

18

19

20

21

22

23

24

25

26

27

28

TABLE 2-3 Ex. No. Structural Formula 29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

TABLE 2-4 Ex. No. Structural Formula 49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

TABLE 2-5 Ex. No. Structural Formula 67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

TABLE 2-6 Ex. No. Structural Formula 83

84

85

86

87

88

89

90

91

92

What is claimed is:
 1. A compound of formula (I), a pharmacologicallyacceptable salt or hydrates thereof:

wherein A in formula (I) is a hydrogen atom, halogen atom, hydroxylgroup, C1-C4 alkyl group or alkoxy group which may be substituted with ahalogen atom, cyano group, —(CO)kNR²R³ (wherein, R² and R³ are the sameas or different from each other and each means hydrogen atom or a C1-C4alkyl group which may be substituted with a halogen atom; and k means 0or 1), C2-C4 alkenyl group or alkynyl group which may have asubstituent, or a phenyl group or phenoxy group which may have asubstituent selected from the following group A; B is an aryl group ormonocyclic heteroaryl group which may have a substituent selected fromthe following group A, or

(wherein, the ring Q is an aromatic ring which may have one or twonitrogen atoms; the ring M is an unsaturated C5-C12 monocyclic orpolycyclic ring which shares a double bond with the ring Q, and the ringmay have 1 to 4 hetero atoms selected from nitrogen atom, oxygen atomand sulfur atom; the ring Q and the ring M may share nitrogen atom witheach other; and the ring Q and the ring M may each have a substituentselected from the following group A); K is a single bond or —(CR⁴R⁵)m—(wherein, R⁴ and R⁵ are the same as or different from each other andeach means hydrogen atom or a C1-C4 alkyl group; and m is an integer of1 or 2); one of T, U, V, W, X and Y is a nitrogen atom and the rest are═C(D)— (wherein D is a hydrogen atom, halogen atom, hydroxyl group,C1-C4 alkyl group or alkoxy group which may be substituted by a halogenatom, cyano group, —(CO)nNR⁶R⁷ (wherein R⁶ and R⁷ are the same as ordifferent from each other and each means a hydrogen atom or a C1-C4alkyl group which may be substituted with a halogen atom; and n means 0or 1), or a C2-C4 alkenyl group or alkynyl group which may have asubstituent); Z is a single bond or —CO—NH—; R₁ is a hydrogen atom or aC1-C4 alkyl group; and means a single or double bond, Group A is ahalogen atom, hydroxyl group, C1-C4 alkyl group or alkoxy group whichmay be substituted by a halogen atom, cyano group, —R⁸R⁹N(NH)p— (whereinR⁸ and R⁹ are the same as or different from each other and each meanshydrogen atom or a C1-C4 alkyl group which may be substituted with ahalogen atom; and p means 0 or 1, and R⁸ and R⁹ may be combined with thenitrogen atom to which they bound to form a 5- or 6-membered ring whichmay further include a nitrogen atom, oxygen atom or sulfur atom and mayhave a substituent), an aminosulfonyl group which may be substitutedwith one or two C1-C4 alkyl groups, an optionally substituted C1-C8 acylgroup, a C1-C4 alkyl-S(O)s-C1-C4 alkylene group (wherein s means aninteger of 0, 1 or 2), a phenylsulfonylamino group which may have aC1-C4 alkyl or a substituent, —(CO)qNR¹⁰R¹¹ (wherein R¹⁰ and R¹¹ are thesame as or different from each other and each means hydrogen atom or aC1-C4 alkyl group which may be substituted with an amino group which maybe substituted with a halogen atom or a C1-C4 alkyl group; and q means 0or 1), or an aryl or heteroaryl group which may have a substituent,provided that the following cases are excluded: 1) A and D are bothhydrogen atoms; 2) when Y is a nitrogen atom, then T, U, V, X and Y are═C(D²)—, wherein D² is a hydrogen atom, K and Z are single bonds, A is ahydroxyl group, and B is a p-tolyl group.
 2. The compound, thepharmacologically acceptable salt or hydrates thereof according to claim1, wherein Z is a single bond.
 3. The compound, the pharmacologicallyacceptable salt or hydrates thereof according to claim 1, wherein A is ahalogen atom, a C1-C4 alkyl or alkoxy group which may be substitutedwith a halogen atom, cyano group, —(CO)rNR¹²R¹³ (where R¹² and R¹³ arethe same as or different from each other and each means hydrogen atom ora C1-C4 alkyl group which may be substituted with a halogen atom; and rmeans 0 or 1) or a C2-C4 alkenyl group or alkynyl group which may have asubstituent.
 4. The compound, the pharmacologically acceptable salt orhydrates thereof according to claim 1, wherein only one of T, W and Y isa nitrogen atom.
 5. A quinoline compound represented by the formula:

wherein Y₁ and W₁ are different from each other and each means anitrogen atom or ═C(D³)— (wherein, D³ is hydrogen atom, halogen atom,hydroxyl group, C1-C4 alkyl group or alkoxy group which may besubstituted with a halogen atom, cyano group or —(CO)nNR⁶R⁷ (wherein, R⁶and R⁷ are the same as or different from each other and each means ahydrogen atom or a C1-C4 alkyl group which may be substituted with ahalogen atom; and n denotes 0 or 1); E is a halogen atom, cyano group ora C1-C4 alkyl group which may be substituted with a halogen atom; J isan amino group which may have a protecting group or a carboxyl groupwhich may have a protecting group; and G¹ is a hydrogen atom, halogenatom, hydroxyl group, a C1-C4 alkyl group or alkoxy group which may besubstituted with a halogen atom, cyano group, —(CO)tNR¹⁴R¹⁵ (wherein,R¹⁴ and R¹⁵ are the same as or different from each other and each meanshydrogen atom or a C1-C4 alkyl group which may be substituted with ahalogen atom; and t denotes 0 or 1) or a C2-C4 alkenyl group or alkynylgroup which may have a substituent or a salt thereof.
 6. A process forproducing a compound represented by the formula (IV):

wherein E¹ is a halogen atom; R¹⁶ is a carboxyl-protecting group; G² isa hydrogen atom, halogen atom, hydroxyl group or a C1-C4 alkyl group oralkoxy group which may be substituted with a halogen atom, wherein saidmethod comprises the steps of: reducing a compound represented byformula (III):

(wherein E¹ is a halogen atom; E² is chlorine atom or bromine atom; R¹⁶is a carboxyl-protecting group; G² is hydrogen atom, a halogen atom,hydroxyl group, or a C1-C4 alkyl group or alkoxy group which may besubstituted with a halogen atom) with tin, zinc or iron; and producingsaid compound of formula (IV).
 7. A pharmaceutical compositioncomprising: the compound, the pharmacologically acceptable salt orhydrates thereof as claimed in claim 1 as an active ingredient; and apharmaceutically acceptable carrier.
 8. A method for treating a diseaseagainst which an antiangiogenic effect is efficacious for the treatment,said method comprising: administering a pharmacologically effectiveamount of the compound, the pharmacologically acceptable salt orhydrates thereof as claimed in claim 1 to a patient in need thereof. 9.The method according to claim 8, wherein the disease is cancer,cancer-metastasis, diabetic retinopathy, rheumatic arthritis orhematoma.